Vascular diseases of the liver are less common than many other conditions, but they have assumed increasing importance in the differential diagnosis of liver disorders—in part because of improved ability to diagnose the more common chronic hepatitic and biliary liver diseases, and in part because vascular damage can play a role in the pathophysiology of virtually all liver disorders. In most liver diseases, the primary injury affects hepatocytes or duct cells, and the vascular damage is secondary. However, there are many primary disorders of the hepatic vasculature, and these are the focus of this chapter. Hepatic vascular disease is classified according to the size and type of blood vessels involved, because various etiologic types of liver disease target different portions of the hepatic vasculature.
The vasculature of the liver is unique in that it has two afferent supplies, arterial and splanchnic. The hepatic artery accounts for 30% to 40% and the portal vein accounts 60% to 70% of the hepatic blood supply. The obligate pathophysiologic outcome of disease affecting the afferent circulation is downstream ischemia. The degrees to which these two circulations are compromised account for the great variety of histologic patterns produced by vascular disease. The patterns reflect the number and size of afferent vessels involved and whether obstruction is rapid or slow. Compromise of hepatic venous outflow also creates ischemic injury, because blood flow through the liver is impeded. In this situation, however, localized or more general mechanical compression may also contribute to hepatic damage, depending on the severity of outflow obstruction.
As the predominant cell type in the liver, hepatocytes can manifest two levels of ischemic injury. Atrophy is a reduction of cell size that occurs in response to mild ischemia; it is typically seen with pure portal vein obstruction or isolated mild venous outflow obstruction. If portal vein compromise is accompanied by damage to the hepatic artery feeding the same region or to the regional hepatic vein, hepatocellular death occurs. Primary obstruction of the hepatic veins, small or large, also leads to hepatocellular death. After hepatocytes die, local collapse of the tissue leads to secondary fibrosis, a lesion referred to as parenchymal extinction. When parenchymal extinction is widespread, the accumulated lesions are recognized as cirrhosis (see Chapter 50 for greater detail). Considering that the pathology of hepatitis includes vascular damage, it may be a challenge to discern whether histologic injury to the hepatic parenchyma is a result of primary vascular disease or part of a broader pattern of hepatitis that evolves to cirrhosis.
If primary vascular injury leads to regional hepatocellular atrophy without fibrosis, other well-vascularized areas may regenerate and lead to the development of hepatocellular nodules. The combination of regional atrophy with nearby regeneration occurs in two major histologic patterns: nodular regenerative hyperplasia (NRH), in which the nodules are small, uniform, and diffuse, and large regenerative nodules, in which the nodules are large and irregularly distributed, up to and including focal nodular hyperplasia (FNH).
Hepatic arterial compromise has a direct effect on bile duct epithelial cells, because bile ducts derive their vascular supply exclusively from arteries. The most dramatic example is occlusion of the hepatic artery after liver transplantation, which leads to necrosis of the major bile ducts and loss of the organ.
Hepatic venous outflow obstruction often exhibits mixed features, because thrombi can propagate in a retrograde fashion, and the sluggish intrahepatic blood flow can lead to secondary portal vein thrombosis. This process is discussed further in the section on hepatic vein disease.
Agenesis of the portal vein and large spontaneous portosystemic shunts may be associated with other congenital anomalies. In patients with cirrhosis, spontaneous large-caliber shunts are usually secondary to portal hypertension (see Arterioportal and Arteriovenous Shunts).
The clinical presentation of hepatic vascular disease depends on the location of the obstruction. Obstruction of portal veins is usually clinically silent initially, but severe and prolonged obstruction may lead to varices, usually without ascites or liver failure. Obstruction of hepatic arteries is usually silent but it may result in necrosis of hepatocytes or bile ducts if combined with hypotension or with another vascular lesion, or if it occurs after organ transplantation. Obstruction of hepatic veins tends to cause increased formation of hepatic lymph, leading to ascites and, if severe, splanchnic varices and hepatic failure.
The position of the liver, between the capillary bed of the intestines and the heart, accounts for the important clinical effects of portal hypertension caused by obstruction of blood vessels within the liver. Portal hypertension is commonly classified as either cirrhotic or noncirrhotic, according to the histology of the liver parenchyma. Before 1945, approximately 40% of patients with portal hypertension were thought to have noncirrhotic portal hypertension, but in recent years, that percentage has decreased to less than 1%. The decline in noncirrhotic portal hypertension is largely the result of recognition that although the fibrosis of cirrhosis is largely reversible after successful treatment of the primary liver disease, the abnormalities in vascular pathophysiology remain. Specifically, patients with features of cirrhosis on biopsy specimens may subsequently have biopsy specimens that lack histologic criteria of cirrhosis. However, these patients often continue to have portal hypertension because more normal portal and hepatic vein anatomy may never be completely restored. Therefore, patients with “regressed” cirrhosis fall into the category of hepatic vascular disease and merit discussion in this chapter.
Although hepatic vessels have some unique properties, their response to stress is similar to that in other organs. Therefore, the cause of hepatic vascular disease may be considered in terms of the elements of the Virchow triad: vascular injury, obstruction, and hypercoagulable states. Tables 51.1 through 51.3 delineate the reported clinical settings in which venous thrombosis in the liver can occur; selected citations are given with the tables.
|PV Thrombosis||HV Thrombosis||References|
|Latent myeloproliferative disease||+||+|
|Paroxysmal nocturnal hemoglobinuria||+||+|
|Chronic myeloid leukemia||+||+|
|Protein C deficiency||+||+|
|Protein S deficiency||+||+|
|Antithrombin III deficiency||+||+|
|Factor II G20210A||+||+|
|Factor V Leiden||+||+|
|Heparin cofactor II deficiency||+||−|
|Other Hypercoagulable States|
|Oral contraceptive therapy||+||+|
|Lupus anticoagulant or antiphospholipid antibodies||+||+|
|Idiopathic thrombocytopenic purpura||−||+|
|PV Thrombosis or Obstruction||HV Thrombosis||References|
|Carcinoma of pancreas||+||−|
|Renal cell carcinoma||−||+|
|Leiomyosarcoma or leiomyoma||−||+|
|Other Stasis Lesions|
|Congestive heart failure||−||+|
|Membranous obstruction of inferior vena cava||−||+|
|Superior vena cava obstruction||−||+|
|Other congenital anomalies||−||+|
|Umbilical cord redundancy or placental thrombosis||−||+|
|Sickle cell disease||−||+|
|PV Thrombosis||HV Thrombosis||References|
|Congenital hepatic fibrosis||+||−|
|Hematopoietic cell transplantation||+||−|
|Inflammatory bowel disease||+||−|
|Vasculitis or tissue inflammation||−||+|
|Idiopathic granulomatous venulitis||−||+|
|Inflammatory bowel disease||−||+|
|Mixed connective tissue disease||−||+|
|5q Deletion syndrome and hypereosinophilia||−||+|
Identification of normal vascular structures of the liver merits a brief discussion. Portal veins divide dichotomously at acute angles and are accompanied by arteries and bile ducts. At the most terminal portions of the portal tree, portal veins disappear, leaving only the last traces of the hepatic artery/bile duct pairings. The smallest portal tracts, without or with portal veins, may be identified in Masson trichrome–stained sections on the basis of the delicate investment of connective tissue around the portal tract. Large hepatic veins also divide dichotomously, but the smallest hepatic veins enter larger branches at a right angle, similar to the bristles of a brush. There also is a slight preponderance of portal tracts versus hepatic veins within the hepatic parenchyma. In some disorders, portal veins are obliterated with local atrophy of the adjacent parenchyma, so that hepatic veins often “migrate” to the periportal region. When parenchymal extinction has occurred, an hepatic vein may be “tethered” to a portal tract by a short fibrous septum. For these reasons, identification of hepatic veins in some instances may be a challenge, one that can be solved by identification of elastic fibers in the wall of the vein or by tracing the vessel through multiple levels to a more recognizable centrilobular location within the parenchyma.
In the normal liver, lymphatic channels within portal tracts are difficult to identify, because they have few or no muscle fibers and are not dilated on histologic sections. Closer to the hepatic hilum, larger lymphatic channels may be identified and valves may be seen. When the hepatic vasculature is compromised, however, dilated lymphatic channels in the more distal portal tract distribution may become prominent. In cirrhosis, there may be an abundance of lymphatic channels within the fibrous septa, identified in part by the absence of erythrocytes in their lumina. Whether normal or abnormal, lymphatic endothelium stains positive with D2-40, whereas venous endothelium does not.
Portal Vein Disease (Portal Vein Obstruction)
Obstruction of large portal veins most often occurs in adults with symptomatic cirrhosis, and the portal vein lesion is discovered during imaging studies. In the absence of cirrhosis, large portal vein obstruction may develop as a primary event, often termed idiopathic portal hypertension (IPH), or secondary to inflammatory conditions involving the portal vein, such as schistosomiasis or sarcoidosis. In these conditions, the portal vein thrombosis is typically silent until the onset of bleeding varices; ascites is usually absent. During the asymptomatic period, clinical evidence of portal hypertension, especially splenomegaly or thrombocytopenia, often leads to the diagnosis through imaging studies. The portal vein may appear to be absent, and multiple hilar collaterals may result in an appearance termed cavernous transformation. Large collaterals develop in the round ligament in 5% of patients; rarely, this manifests as a bruit or an umbilical caput medusa. Round ligament collaterals are dilated paraumbilical veins that communicate with the left portal vein. Large collaterals between the extrahepatic portal vein and the renal or adrenal veins are frequently seen. Numerous smaller collaterals are often seen during imaging or abdominal surgery. Secondary aneurysmal dilatation of the portal vein may also occur.
In contrast to this type of indolent natural history, acute portal vein obstruction accompanied by thrombosis of the mesenteric veins can be catastrophic and can lead to infarction of the intestines. This sequence often occurs in the setting of abdominal sepsis, trauma with vascular injury, cirrhosis, or growth of hepatocellular carcinoma into the main portal vein.
The portal vein branches are hypoplastic in patients with persistent ductus venosus or other congenital anomalies of the major vessels. Hepatic encephalopathy with hyperammonemia may be a presenting feature when portosystemic shunting is prominent.
Obstruction confined to the small portal veins is a rare cause of portal hypertension and tends to be milder than that seen in patients with large portal vein obstruction. Consideration is given at the end of this chapter to hepatoportal sclerosis, a condition that appears to arise from chronic damage to the large and small intrahepatic portal veins.
Large Portal Veins
Most often, portal vein obstruction occurs in the setting of another hepatic disease, particularly cirrhosis. Beyond that, thrombosis is the most frequent mechanism of large portal vein obstruction, again following the Virchow triad of thrombosis secondary to obstruction, venous inflammation, or a hypercoagulable state (see Tables 51.1 through 51.3 ). Hypercoagulable states causing portal vein obstruction may involve inherited abnormalities of the clotting cascade or acquired abnormalities of the platelets, as in polycythemia vera or other myeloproliferative diseases (see Table 51.1 ). Coincidental hypercoagulable states have also been documented to contribute to thrombosis, even when cirrhosis is present.
Portal vein obstruction may also be related to the presence of tumor, either in the hepatic hilum and growing into the portal vein (typically hepatocellular carcinoma) or in the pancreas, or to small portal vein disease in early primary biliary cirrhosis. Injury to the portal vein vasculature may be caused by a hilar bile leak in primary sclerosing cholangitis or in biliary necrosis after transplantation, or by other events such as splanchnic sepsis, variceal sclerotherapy, or trauma. Trauma may result from blunt abdominal injury or from surgical interventions such as splenectomy, umbilical vein catheterization, portacaval shunt, insertion of a transjugular intrahepatic portosystemic shunt (TIPS), or a Kasai portoenterostomy procedure.
Small Portal Veins
Obliteration of small portal veins (obliterative portal venopathy) may develop secondary to local inflammation, thrombosis, congestive portal venopathy, or toxic injury. Local inflammation is important in any disease with portal inflammation, including chronic hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, sarcoidosis, polyarteritis nodosa, and congenital hepatic fibrosis. Thrombosis may occur as a result of retrograde propagation of thrombi from hepatic veins or in response to sluggish and reversed blood flow, usually in cirrhotic livers. Also in cirrhotic livers, high intrahepatic pressure causes congestive venous injury. A variety of vasculotoxins, including azathioprine, cyclophosphamide, methotrexate, and arsenic, can cause endothelial injury and secondary luminal obliteration. In some geographic regions, schistosomiasis is the most frequent cause of portal vein disease and portal hypertension. The vascular changes in cirrhosis are discussed in Chapter 50 .
Granulomas in sarcoidosis can cause phlebitis of small portal veins. Medium-sized hepatic veins may also be affected. In most patients, granulomas in the portal tracts or associated portal fibrosis can cause presinusoidal resistance and portal hypertension but not cirrhosis. NRH and portal vein thrombosis may occur.
Portal vein thrombus is usually evident only in the healed state, after recanalization and fibrosis have already occurred. The healing process may be almost complete, so that no residual changes, or only slight pearly thickening of the intima, is seen grossly. In other instances, residual high-grade obstruction causes marked intraluminal fibrosis containing numerous racemose channels ( Fig. 51.1 ). Thrombi in large and medium-sized portal veins may recanalize almost completely, leaving a layer of residual intimal fibrosis ( Fig. 51.2 ), or they may remain largely occluded ( Fig. 51.3 ). Multiple layers of collagen indicate recurrent thrombosis. As thrombi heal with a granulation tissue response, small arteries are often seen within the neointima. When thrombosis or inflammatory injury involves small portal veins, the vein walls usually disappear completely within a few weeks after the inciting event. The elastic trichrome stain is better than Masson trichrome for identifying residua of vein walls, which are marked by the location of muscle bundles or variation in the elastic fibers.
After organization of a thrombotic or inflammatory event, obliterated small portal veins have a nonspecific appearance, but several clues may indicate the cause of the original lesion. Portal granulomas may be seen in sarcoidosis and primary biliary cirrhosis; duct paucity favors the latter ( Fig. 51.4 ). Granulomas in sarcoidosis are usually numerous, but in inactive disease, they may resorb, making diagnosis difficult. Eggs of Schistosoma species may occur either with or without granulomatous inflammation ( Fig. 51.5 ). Eggs are few in number with Schistosoma mansoni and numerous with S. japonicum. Active or healed arteritis may suggest polyarteritis nodosa or another rheumatologic condition. Irregular and dilated ducts (Von Meyenburg complexes) are found in most portal tracts in cases of congenital hepatic fibrosis and in occasional portal tracts in polycystic disease. Thorotrast deposits in portal macrophages may be associated with obliteration of small portal veins and noncirrhotic portal hypertension ( Fig. 51.6 ). If marked parenchymal congestion or obstruction of hepatic veins is observed, the portal vein blockage is likely secondary to stasis, with thrombosis.
Patients with noncirrhotic portal hypertension usually have portal vein intimal fibrosis and delicate septa, suggesting regressed cirrhosis and superimposed portal vein thrombosis or congestive portal venopathy. After portal vein obliteration, the liver parenchyma becomes atrophic, with crowding of the portal tracts. If the region of sinusoidal dilatation is focal, it is called an infarct of Zahn (see Sinusoidal Dilatation). Atrophy may be either uniform or mixed with small regenerative nodules in a pattern referred to as NRH (discussed later).
Causes of portal hypertension in the absence of cirrhosis are variable. Worldwide, schistosomiasis is the most common cause. Alcohol-induced liver disease, inherited metabolic diseases, and autoimmune liver diseases can cause portal hypertension at the precirrhotic stage. However, the most important differential diagnosis is cirrhosis.
Exclusion of Cirrhosis and Regressed Cirrhosis
The diagnosis of portal vein disease does not rely on the histologic appearance alone but requires consideration of clinical and imaging information. The most useful task in a patient with portal hypertension is to confirm the presence or absence of cirrhosis, including the possibility of regressed cirrhosis (discussed in Chapter 50 ). This allows the investigation to be directed at the most likely cause of the cirrhosis.
Of course, biopsy specimen size is important in providing the pathologist with enough evidence to accurately exclude cirrhosis (see Chapter 50 ). Cirrhosis, particularly when highly regressed, is frequently missed when biopsy specimens are shorter than 2 cm in length. Regressed cirrhosis should be suspected when there is a reduction of both portal and hepatic veins, delicate remnants of fibrous septa, and an irregular arrangement of portal structures and hepatic veins, typically with hepatic veins in close approximation to portal tracts. If, in cirrhosis, small portal veins are obliterated, the acinar arrangement is normal (usually), and hepatic veins are patent, the disease likely involves only the portal veins or portal tracts. Irregularity of parenchymal atrophy and hyperplasia (i.e., NRH) suggests small vessel disease, even if this is not represented in the biopsy specimen. Similar changes may occur adjacent to mass lesions, including neoplasms and abscesses.
Patients may be diagnosed with idiopathic or noncirrhotic portal hypertension on the basis of imaging studies (no identifiable alteration in hepatic features) or biopsy evidence (no identifiable abnormality in hepatic microanatomy that would suggest regressed cirrhosis). In the latter instance, the limited amount of tissue in liver biopsy specimens may make identification of regressed cirrhosis difficult. Alternatively, the histologic manifestations of regressed cirrhosis may be termed incomplete septal cirrhosis or hepatoportal sclerosis , depending on the location of residual fibrous tissue (delicate parenchymal septa in the former, portal tracts alone in the latter). Incomplete septal cirrhosis is discussed in Chapter 50 ; hepatoportal sclerosis is discussed later in this chapter. Last, “IPH” identified clinically may represent a mixture of diseases or one disease with various histologic manifestations.
Exclusion of Portal Vein Thrombosis
Liver biopsy is seldom indicated for identification of large portal vein disease, because peripheral biopsies do not sample these vessels. Recanalization of large portal vein thrombi make these lesions elusive from a clinical point of view. Prior thrombosis is suspected when there is prominent intimal fibrosis of portal veins, especially those larger than 200 µm in diameter. No specific histologic features can be used to diagnose hypercoagulable states. However, hepatomegaly, marked splenomegaly, and extramedullary hematopoiesis in the liver are often found in myeloproliferative disease, even in patients without hepatic vascular disease.
Obliteration of small portal veins is nonspecific. Lesions associated with inflammatory obliteration of small portal veins should be sought, including duct lesions of primary biliary cirrhosis, granulomas of sarcoidosis and schistosomiasis, and arteritis. Obliteration of subcapsular small portal veins is a common event among aged individuals. However, the finding that the majority of small portal veins are missing is likely to be significant. Congestive portal venopathy and postthrombotic scarring are often identical in appearance. Thrombosis, when present, involves many small and medium-sized portal veins, whereas congestive lesions are usually patchy in distribution and confined to the small veins. This criterion is useful only when examining large samples, such as liver explant specimens. Congestive lesions are more likely to occur in cirrhotic livers, where high-grade hepatic vein outflow obstruction is characteristically present.
Exclusion of Parasitic Disease
Schistosomes are trematode flukes. Some species may involve the liver, such as S. japonicum in Asia and S. mansoni in Africa and South America. Liver disease in schistosomiasis is attributed to the entrapment of parasitic ova in portal veins. The secretion of ova induces a granulomatous reaction and collagen deposition. In an individual with severe infestation of schistosomes, marked portal fibrosis ensues; this condition is known as Symmers pipestem fibrosis. The clinical presentation of hepatic schistosomiasis mimics IPH in that variceal bleeding and massive splenomegaly with normal liver test results and no ascites are common manifestations.
The hepatic arterial system may be involved by systemic diseases such as amyloidosis or polyarteritis nodosa. Atherosclerosis may affect the extrahepatic arterial trunk, and the intrahepatic arteries may exhibit hyaline arteriosclerosis in older individuals. Atherosclerotic emboli may occasionally lodge in the hepatic arterial circulation. Regardless of cause, arterial disease in the liver is seldom symptomatic, mainly because of the smaller contribution of the hepatic artery to hepatic blood flow and compensation from portal veins. However, in patients with hypotension or congestive heart failure, infarcts or liver failure may occur as a result of regional arterial disease. Moreover, as noted earlier, arterial compromise leading to ischemic damage to the biliary tree may lead to failure of the entire organ.
Liver Injury Resulting from Ischemia and Shock
Forward-flow circulatory compromise to the liver may be the result of heart failure caused by acute myocardial infarction or circulatory shock resulting from hypovolemia, severe trauma, or sepsis. Patients with circulatory shock have both low arterial blood pressure and reduced oxygen tension in the portal veins. Typically, a sharp rise in serum aminotransferases, with or without liver failure develops in patients with shock. Enzymes typically normalize rapidly in those patients who survive. Hepatic infarction has also been associated with Budd-Chiari syndrome, hepatic trauma, hepatic transplantation, hepatic catheterization, laparoscopic cholecystectomy, TIPS insertion, and alcohol injection. A variety of hypercoagulable states and vascular injury syndromes may cause liver ischemia, including disseminated intravascular coagulation (DIC), sepsis, toxemia of pregnancy, the HELLP syndrome (i.e., hemolysis, elevated liver enzymes, and low platelet count), arteritis, sickle cell disease, and oral contraceptive use.
Left-sided cardiac failure or shock may lead to the development of sharply demarcated zones of coagulative necrosis ( Fig. 51.7 ). Zone 3 is usually most susceptible to the effects of ischemia, giving rise to the term centrilobular necrosis . Rarely, isolated zone 2 necrosis is seen. Single-cell calcification may occur. Apoptotic bodies are usually observed in the zone between healthy and coagulated hepatocytes. Zone 1 necrosis is typical of diseases that produce intravascular fibrin deposition, such as toxemia of pregnancy and DIC. The fibrin in these conditions may be present in arterioles, portal venules, and zone 1 sinusoids. Regardless of cause, a reticulin stain can help identify areas of architectural collapse resulting from loss of hepatocytes.
In the liver, an infarct is defined as ischemic necrosis involving two or more contiguous and complete acini; both zone 1 and zone 2 must be involved. Infarcts occur when at least two of the following vessels are involved in the same unit of liver tissue: portal vein, hepatic vein, and hepatic artery ( Fig. 51.8 ). In the presence of hypotension, lesser degrees of vascular obstruction are necessary to produce infarction. Often, no vascular obstruction can be identified.
The differential diagnosis of zone 3 necrosis includes drug-induced injury, particularly with acetaminophen or cocaine. Amanita phalloides (mushroom) hepatotoxicity also shows zone 3 coagulative necrosis. Herpes virus infection results in necrosis that resembles infarcts except that the margins of necrosis do not follow the normal hepatic acinar landmarks and viral inclusions are usually visible. Atrophy and sinusoidal dilatation suggest underlying chronic passive congestion, as seen in patients with right-sided heart failure. (see Hepatic Vein Disease). Livers with marked zone 3 atrophy and/or zone 3 necrosis, combined with zone 3 hemorrhage from retrograde congestion (as from right-sided heart failure), often have a gross appearance that resembles the cut surface of a nutmeg and is termed “nutmeg liver” ( Fig. 51.9 ). The combination on microscopy of centrilobular necrosis from forward-flow ischemia with hemorrhage from retrograde congestion is termed centrilobular hemorrhagic necrosis.
Large- and medium-sized hepatic arteries may be affected in polyarteritis, Wegener granulomatosis, and rheumatoid arthritis. The arteritis is usually clinically silent, although hepatic rupture has been reported. Small vessel arteritis, as in systemic lupus erythematosus (SLE) or rheumatoid arthritis, is also usually clinically silent but may result in obliteration of adjacent portal veins, leading to NRH and portal hypertension. The histology of the various types of arteritis is the same in the liver as in other organs.
Hepatic Artery Obstruction
Hepatic artery obstruction, caused by thrombosis, arteritis, or surgical ligation, is usually well-tolerated unless hypotension or DIC is also present, in which case infarction may occur. After liver transplantation, however, the ducts of the implanted liver do not have the rich, anastomosing arterial bed that was present in the native liver and therefore are dependent on blood flow from an intact hepatic artery. Thrombosis of this vessel may lead to ischemia of the bile ducts, leakage of bile, and necrosis of the perihilar parenchyma ( Fig. 51.10 ). The resulting necrotic debris often harbors Candida or other microorganisms. Partial biliary obstruction (stricture or bile cast syndrome) often leads to liver failure, necessitating replacement of the organ. Hepatic artery cannulation and infusion with floxuridine or other agents may also lead to biliary ischemia and eventually to large duct stenosis.
Arterioportal and Arteriovenous Shunts
Large shunts between the splanchnic artery and the portal or the hepatic vein most commonly develop many months or years after penetrating trauma (e.g., gunshot wound, liver biopsy). Large shunts may also occur as the result of a developmental anomaly. In some patients, they are found early in life; in others, especially with hereditary hemorrhagic telangiectasia, the shunts develop progressively during several decades. Increased arterial flow to the liver may be inapparent but can manifest with a bruit, high-output congestive heart failure, ascites, diarrhea, weight loss, protein-losing enteropathy, or hemobilia. When the shunt involves the portal vein, portal hypertension is the most important effect. The diagnosis depends on detecting a dilated high-flow channel by Doppler ultrasonography or other imaging studies. On arteriography, one may see an apparent doubling of the vascular tree, possibly because of early retrograde filling of the portal veins that run parallel to the arteries. The portal vein branches may be obliterated. Histologically, numerous congested capillaries and arterioles, either within or adjacent to portal tracts, is characteristic. Hereditary hemorrhagic telangiectasia is discussed further in Chapter 54 .
The sinusoids play a critical role as conduits of blood and nutrients to hepatocytes. The normal sinusoidal wall is composed of highly fenestrated endothelial cells and a delicate fibrillar matrix without a well-defined basement membrane or occlusive pericytes. Stellate cells reside in the subendothelial space of Disse. These cells contain droplets of retinoyl esters and produce collagen in response to inflammation. They also have contractile properties that are activated by endothelin 1 and inhibited by nitric oxide. The sinusoids must adapt to physiologic and pathologic alterations in arterial and venous blood flow. In chronic liver diseases, the stellate cells are activated and transformed into myofibroblasts, which lay down extracellular matrix causing hepatic fibrosis and, through their contractile activity, increase resistance to blood flow through the sinuosoids. Many types of disorders involve histologic changes of the sinusoids and small veins.
Sinusoidal diameter and hepatocyte size are fairly uniform within the normal liver, although there is a slight widening of sinusoidal diameter in zone 3. This uniformity is lost when there is local obstruction of portal or hepatic veins, which leads to hepatocellular atrophy and sinusoidal dilatation and is often accompanied by a local compensatory increase in arterial blood flow. The resulting localized increase in the blood space is seen macroscopically as a darkened region of liver parenchyma, termed infarct of Zahn . When many adjacent obstructive portal vein lesions occur, hepatocyte atrophy causes the portal tracts to become crowded together. Typically, these lesions are seen adjacent to neoplasms, which compromise regional blood flow because of their compressive mass effect, or with focal portal vein thrombosis.
In chronic congestive heart failure and constrictive pericarditis with retrograde impediment to hepatic venous outflow, a diffuse increase in sinusoidal pressure leads to zone 3 hepatocellular atrophy and sinusoidal dilatation ( Fig. 51.11 ). With time, pericellular fibrosis develops, obliterating small hepatic veins; rarely, cirrhosis that features a pericentral pattern of fibrous septation develops. Sinusoidal dilatation is also seen in patients with chronic wasting illnesses such as tuberculosis or acquired immunodeficiency syndrome (AIDS) ; with malignancies, notably Hodgkin disease or renal cell carcinoma ; and within nodules of severe cirrhosis. Dilatation of zone 1 and 2 sinusoids occurs during pregnancy and in women taking oral contraceptives. The mechanism of this effect may be related to mild diffuse angiogenesis and increased arterial blood flow. Sickle cell disease characteristically shows small clumps of sickled red blood cells within sinusoids ( Fig. 51.12 ). In this disease, sinusoidal fibrosis is often seen. Cirrhosis is rare; when present, it is caused by coincidental viral or other liver disease.
A sharp delineation between well-preserved zone 1 hepatocyte plates and atrophic zone 2 and zone 3 plates, with sinusoidal dilatation, may result not from retrograde obstruction to blood flow but from forward-flow underperfusion. This underperfusion may be caused by vascular disease affecting the portal veins and hepatic arteries (discussed earlier) or may occur in the setting of modest compromise of the vascular anastomoses in a hepatic transplantation graft. Finally, parenchymal lesions that create local scarring and “traction” on adjacent regions of the liver may create secondary sinusoidal dilatation unrelated to the physiology of blood flow. The most dramatic features of “traction dilatation” are seen in tertiary syphilis, in which gummatous lesions create a characteristic hepar lobatum macroscopically, with interspersed fibrotic scars and dilated sinusoidal spaces in the hepatic parenchyma surrounding the gummata. More limited examples may be seen adjacent to other mass lesions of the liver if there is scarring of the surrounding parenchyma.
Peliosis hepatis is defined as the presence of blood-filled spaces in the liver resulting from focal rupture of sinusoidal walls. The term was initially used to describe grossly visible lesions, but it is now also applied to microscopic lesions. Severe sinusoidal dilatation may resemble peliosis. The difference, by definition, is that peliosis is caused by rupture of the sinusoidal walls, whereas these walls are intact in sinusoidal dilatation.
Peliosis may be minimal, asymptomatic, and grossly inapparent or severe in cases of cholestasis, liver failure, portal hypertension, development of a mass lesion, or spontaneous rupture. Calcifications may develop and can be seen radiologically. Peliosis has been associated with exposure to a variety of drugs, including anabolic steroids, tamoxifen, corticosteroids, azathioprine, methotrexate, 6-thioguanine, 6-mercaptopurine, vinyl chloride, arsenic, and Thorotrast, and it may be seen in hairy cell leukemia. Bartonella infection can cause bacillary peliosis, which occurs mainly in immunosuppressed patients.
The endothelial lining may be lost during lesion development, but it is usually regained in chronic lesions. Severe peliosis is characterized by separation of the sinusoidal parenchyma from the portal tracts. The portal tracts appear similar to exfoliated branches of a tree in winter ( Fig. 51.13 ). In Bartonella infection (discussed later), the organisms may be seen as a vague haze on hematoxylin and eosin (H&E)-stained sections but are well visualized with a Warthin-Starry stain. Peliotic change to the sinusoidal vasculature may also be observed in various tumors, particularly hepatocellular adenoma, hepatocellular carcinoma, and angiosarcoma. Therefore, it is important to examine the surrounding liver and the endothelial lining for these lesions.
Peliosis may be mistaken for hemangioma. However, in the latter condition, the blood-filled spaces are lined by a robust vascular wall, and the portal tracts do not extend into the blood-filled cavities, as they do in peliosis.
Infection with Bartonella (formerly known as Rochalimaea ) may manifest as vascular proliferative lesions in patients with HIV infection and other immunocompromised hosts. Bacillary angiomatosis may affect the liver (called bacillary peliosis hepatis), spleen (bacillary splenitis), and skin. Necrotizing granulomatous disease is the other form of Bartonella infection. In patients with malignancy who are receiving chemotherapy or are immunocompromised caused by HIV infection or organ transplantation, Bartonella infection should be considered in the differential diagnosis of a febrile illness.
Bacillary peliosis of the liver generates peliotic foci of necrosis within the parenchyma, characterized by multiple cystic blood-filled spaces or lakes. Although peliosis has been described in patients receiving azathioprine and cyclosporine after organ transplantation and in those receiving anabolic androgenic and estrogenic steroids, the finding of aggregates of Bartonella bacilli highlighted by a Warthin-Starry silver stain with a mixture of inflammatory cells in the background of fibromyxoid stroma helps support a diagnosis of infection caused by Bartonella. Serologic analysis, culture, and, ultimately, polymerase chain reaction (PCR) testing of peripheral blood or liver tissue may be confirmatory.
Sinusoidal Injury, Fibrosis, and Arterialization
Because of their close proximity to hepatocytes, sinusoids are injured in all forms of acute and chronic hepatitis. Injury is most often appreciated when contiguous hepatocytes are lost, a phenomenon referred to as parenchymal extinction . Hepatocyte loss that spans across all acinar zones is termed bridging necrosis . When necrotic regions collapse, the portal tracts and veins become closely approximated to each other. This is readily appreciated with a reticulin stain, because collapse of the intervening parenchymal plates with complete loss of hepatocytes is evident. If dropout involves only zone 3 hepatocytes, the liver cell plates may be “empty,” but there may be little or no collapse of the reticulin framework, resulting in a lesion termed “evacuation of the liver cell plates.” This lesion is most commonly seen in patients with allograft rejection, acetaminophen toxicity, or chronic hepatitis.
Sinusoids are normally lined by CD34-negative endothelial cells. In chronic liver disease, the endothelium becomes CD34 positive, first in endothelium near the portal tracts and later throughout the lobules (e.g., in cirrhosis). This is termed arterialization (or capillarization) of the sinusoids. Other features of arterialization include decreased fenestration of the endothelial cells, increased collagen and other matrix proteins in the space of Disse, and loss of microvilli on the surface of hepatocytes. Sinusoidal fibrosis is detected in early and active disease, usually in association with activated hepatic stellate cells, which stain positively for α-smooth muscle actin.
Sinusoidal fibrosis may be found in any type of chronic liver disease, although it is typically most prominent in patients with alcoholic disease, nonalcoholic steatohepatitis, hepatic vein thrombosis, vitamin A toxicity, congenital syphilis, sickle cell disease, or Gaucher disease. CD34-positive sinusoidal endothelial cells are present to a variable degree in cirrhosis, hepatocellular carcinoma, adenomas, FNH, and NRH.
Sinusoidal Obstruction Syndrome (Veno-occlusive Disease)
Sinusoidal obstruction syndrome (SOS) occurs most commonly as a complication of myeloablative regimens that are used to prepare patients for hematopoietic stem cell transplantation (i.e., bone marrow transplantation). Its frequency and severity have decreased during recent years, largely as a result of changing transplantation regimens. SOS is defined by the presence of prominent obstructive, nonthrombotic lesions of the small hepatic veins in individuals exposed to either radiation or a hepatotoxin. The definition has been modified, and the term SOS has replaced the former term, veno-occlusive disease (VOD). Specifically, the initial lesion is caused by injury to the endothelial cells of sinusoids and small veins, leading to hemorrhage into the liver parenchyma and into the walls of hepatic veins. Because of this acute phenomenon, the disorder is termed sinusoidal obstruction syndrome . Among survivors of SOS, the sinusoidal lesions become less apparent with time, and the major residual lesion is fibrous obliteration of small hepatic veins. This residual pattern of disease is the one that was characterized in the original description of VOD ; the acute sinusoidal lesions were not appreciated histologically or experimentally until many years later.
Patients with early disease exhibit tender hepatomegaly, ascites, rapid weight gain, and hepatic failure with elevated serum bilirubin. The onset of this toxic syndrome can be diagnosed on clinical grounds, and percutaneous liver biopsy may be too risky a procedure given the potential of an evolving coagulopathy. If histologic diagnosis is needed to exclude other conditions, transjugular biopsy can provide a tissue sample and enable measurement of the hepatic venous pressure gradient. A gradient greater than 10 mm Hg is considered highly specific for SOS in patients undergoing hematopoietic cell transplantation.
SOS occurs most commonly in patients being prepared for bone marrow transplantation with myeloablative doses of radiomimetic drugs and irradiation. The drugs most often implicated are cyclophosphamide, busulfan, and gemtuzumab ozogamicin (Mylotarg ). Occasionally, SOS develops in patients given low doses of other drugs and toxins, such as azathioprine, cysteamine, dacarbazine, dactinomycin, carmustine (BCNU), 6-mercaptopurine, 6-thioguanine, dimethylbusulfan, cytosine arabinoside, indicine- N -oxide, mustine (methchlorethamine hydrochloride), doxorubicin, urethane, vincristine, mitomycin-C, oxaliplatin, etoposide, arsenic, Thorotrast, and intraarterial flurodeoxyuridine. Patients who survive acute SOS usually recover completely, but the residual lesions of VOD may remain in the liver for a long period. Portal hypertension or cirrhosis is rare. If cirrhosis becomes clinically manifest, it is usually associated with the presence of other disease (e.g., chronic hepatitis C).
The initial description of “VOD” was in subjects exposed to pyrrolizidine alkaloids. These compounds are found in plants of the genera Senecio, Heliotropium, Crotalaria, and many others. Epidemics of pyrollizidine alkaloid toxicity occur mainly in arid climates, where toxin-containing plants may overgrow crops during periods of drought. Livestock may be affected when grazing, and humans may be affected by eating bread derived from these crops. Herbal medicines created from toxic plants, commonly called “bush tea,” can cause severe disease, especially in young children, and death may occur. Cirrhosis can occur in survivors of pyrrolizidine alkaloid–induced VOD.
SOS has also been observed in the use of oxaliplatin to treat colorectal cancer metastatic to liver. The underlying mechanism is thought to be toxic injury to the sinusoidal endothelial cells by oxaliplatin.
During the first 2 weeks of SOS, the liver exhibits marked diffuse hemorrhage. In the early phase, cirrhosis that develops in survivors of pyrrolizidine toxicity is indistinguishable histologically from other causes of cirrhosis not related to SOS.
The early histologic changes, occurring as early as 1 week after cytoreductive or myeloablative therapy, include a widened and edematous subendothelial zone of the terminal hepatic venule that contains entrapped red blood cells, resulting in concentric narrowing of the venular lumina. Clusters of debris from necrotic hepatocytes, dilated and destroyed sinusoids, and hemorrhage into the space of Disse can be seen surrounding the injured terminal hepatic venules ( Fig. 51.14 ). The necrotic debris may also fill the venular lumina. In this early phase, the hepatic veins are often difficult to locate because of the degree of perivenous hemorrhage. Use of special stains, such as Masson trichrome or reticulin, may help demonstrate the presence and location of the hepatic veins. Examination of tissue under polarized light may also help identify collagen bundles that surround the hepatic veins.