Portal vein lesions 637
Extrahepatic portal vein obstruction 638
Congenital anomalies and portosystemic shunts 639
Intrahepatic portal vein lesions 640
Hepatic artery-related lesions 642
Acute hepatic ischaemic necrosis and hepatic infarction 642
Hepatic artery obstruction and ischaemic cholangiopathy 644
Arterial lesions in systemic disease 645
Other arterial lesions 645
Sinusoidal lesions 645
Sinusoidal dilation 646
Peliosis hepatis 646
Other peliotic-like lesions 646
Sinusoidal obstruction syndrome (veno-occlusive disease) 646
Sinusoidal cellular infiltration 647
Amyloidosis and light-chain deposition disease 648
Hepatic vein lesions 649
Normal variations and congenital anomalies 649
Budd–Chiari syndrome 649
Lesions of small hepatic veins 651
Congestive heart failure and constrictive pericarditis 652
Paediatric and developmental vascular lesions 653
Nodular hyperplastic lesions 653
Large regenerative nodules 656
Nodular regenerative hyperplasia 656
Focal nodular hyperplasia and similar lesions 656
Vascular lesions in cirrhosis 660
Vascular diseases of the liver are less common than other liver diseases, such as hepatitides, cholestatic diseases and alcoholic/nonalcoholic fatty liver diseases, but are gaining increasing recognition because of the improved diagnosis of these other diseases, as well as the secondary involvement of vessels in the course of almost all liver diseases. This chapter focuses mainly on primary vascular diseases of the liver using classification based on the type of blood vessels involved, since different aetiologies of vascular liver disease affect respective aspects of the hepatic vasculature.
The unique features of the hepatic vasculature are manifested by two afferent blood supplies: hepatic artery (HA) and portal vein (PV), with the HA transporting 30–40% and the PV transporting up to 60–70% of the oxygenated blood to the liver. Vascular pathology affecting the afferent blood supply leads to ischaemic changes downstream. The degree of ischaemic changes varies, depending on the number and size of afferent blood vessels affected and the timing of the injury. Lesions of hepatic venous outflow also result in ischaemic changes because hepatic circulation is disrupted. The consequence of ischaemia leads to a spectrum of morphological changes of the hepatocytes. When ischaemia is mild, typically seen in pure PV obstruction or pure venous outflow obstruction, hepatocytes become atrophic with reduction in size. Death of hepatocytes is seen in more severe cases such as when damage of PV along with injury to the HA feeding the same region or to the regional hepatic vein occurs.
Since the only blood supply to bile ducts is the HAs, obstruction or occlusion of the HAs imposes dramatic impact on bile duct epithelial cells; for example, thrombosis of the HA after liver transplantation leads to necrosis of the main bile ducts, and graft failure is a common threat.
For the portal venous system, obstruction can occur at any level. This is the common result of most diseases of the PVs. Obstruction of the PV is usually well tolerated, given the dual blood supply in the liver and the development of collateral circulation. Significant and prolonged obstruction increases the resistance to portal blood flow and may result in portal hypertension, the most significant clinical presentation of PV obstruction irrespective of aetiology.
The sinusoids carry blood from HAs and PVs to the terminal hepatic venules. Outflow obstruction or increased inflow pressure from PV or HA can both cause sinusoidal dilation. Sinusoidal obstruction syndrome is associated with chemical and radiation injury to sinusoidal endothelial cells related to bone marrow or haematopoietic stem cell transplantation. Similar changes are also seen in oxaliplatin-based chemotherapeutic treatment for metastatic colorectal cancer to liver. Fibrosis within the sinusoids, especially in the centrizonal region, is characteristic of outflow obstruction such as sinusoidal obstruction syndrome, hepatic vein thrombosis (Budd–Chiari syndrome) and congestive hepatic fibrosis, but is also seen in nonalcoholic steatohepatitis and alcoholic liver disease. Infiltrates of abnormal cell population, neoplastic or non-neoplastic, or amyloid may also be seen within the sinusoidal spaces.
Obstruction of the hepatic veins, also known as Budd–Chiari syndrome, is often caused by thrombosis or phlebitis but can also be caused by secondary compression or invasion from a neoplastic lesion or infectious process outside the veins. Outflow obstruction of hepatic veins by thrombi can also propagate in a retrograde manner, with slow intrahepatic blood flow resulting in secondary thrombosis of the PV. Budd–Chiari syndrome has similar histological features as congestive hepatopathy, which is also known as ‘cardiac sclerosis’ when there is fibrosis and architectural disturbance.
Nodular hyperplastic lesions can arise in response to various types of vascular compromise. This chapter discusses these lesions in detail, including large regenerative nodules, nodular regenerative hyperplasia, focal nodular hyperplasia and cirrhosis.
Portal vein lesions
The portal vein drains blood from the gastrointestinal (GI) tract and spleen to the liver. The diameter of the PV in normal adults without portal hypertension varies between 0.6 and 1.2 cm. Immediately before reaching the liver, the PV divides into the left and the right PVs, which subsequently divide further into anterior and posterior PVs.
Anatomical variants of the PV are frequently seen, the most common being portal trifurcation, with division of the main portal vein into the left, right anterior and right posterior branches and early origin of the right posterior branch directly from the PV. Other anomalies include preduodenal portal vein, which may lead to duodenal obstruction in children and adults. This anomaly may be caused by persistence of portions of the vitelline veins. Preduodenal PV may also be associated with various abnormalities, such as polysplenia, situs inversus and biliary atresia. Other PV abnormalities include intraluminal obstructing valves and portal vein duplication , both of which may cause portal hypertension in children.
The pathological basis of most disorders of the PVs is obstruction of the lumen, which can occur at any level of the portal venous system. The consequences depend on the location, extent and course of the blockage, but PV obstruction is often well tolerated because of the liver’s dual blood supply and development of collateral circulation. Significant and prolonged obstruction increases the resistance to portal blood flow and can lead to portal hypertension, which thus represents the major clinical manifestation of PV obstruction regardless of cause.
Based on the location, portal vein obstruction (PVO) can be divided into extrahepatic and intrahepatic. Although this distinction has pragmatic value, the two categories are not mutually exclusive. Indeed, some have proposed a continuum between extra- and intrahepatic PVO, with involvement depending on the extent and natural history of the initiating thrombosis. In extrahepatic obstruction the blockage occurs primarily in the larger vessels, the portal trunk and its main tributaries ( Figs 11.1 and 11.2 ). Intrahepatic obstruction is a more elusive condition. Noncirrhotic portal fibrosis, idiopathic portal hypertension and noncirrhotic idiopathic portal hypertension are clinical terms defined by the presence of clinical signs of portal hypertension with patent extrahepatic portal veins and no evidence of other common chronic liver disease causing obstruction of the PVs. Subtle differences may exist among these terms, which are differentially used according to respective countries, but may also reflect different underlying aetiologies. Intrahepatic PVO can produce histological changes that may be identical to extrahepatic PVO on biopsy. Obstructive portal venopathy and hepatoportal sclerosis are the histologically related terms. Some cases with noncirrhotic idiopathic portal hypertension have also been identified by the presence of nodular regenerative hyperplasia, and some have suggested that nodular reorganization may result from occlusion of the smallest intrahepatic PV radicles.
Extrahepatic portal vein obstruction
Extrahepatic portal vein obstruction (EHPVO) refers to the obstruction of the extrahepatic PV with or without involvement of the intrahepatic PV branches, splenic vein or superior mesenteric vein. It is a distinct disorder that excludes portal vein thrombosis (PVT) occurring with liver cirrhosis or hepatocellular carcinoma (HCC). EHPVO is principally reserved for a longstanding condition that may lead to cavernous transformation of the PV, which is replaced by a sponge-like mass composed of numerous tortuous venous channels around or within the original obstructed vein (see Fig. 11.1 ).
The clinicopathological manifestations vary greatly, with portal hypertension with splenomegaly as the major consequence of EHPVO. The acute obstructive event is often clinically silent, but it may prompt a sudden episode of ascites, which in turn may spontaneously resolve once collateral circulation develops. Rarely, more serious acute manifestations develop, including severe abdominal pain and GI bleeding, mainly related to mesenteric venous thrombosis and life-threatening intestinal infarction. Recanalization of PVT is common but may be partial. When there is residual stenosis, perihilar cavernous transformation may result (see Fig. 11.1 C ). A portion of the portal vein may also dilate and form an aneurysm. Portal cavernoma cholangiopathy, or ‘portal biliopathy’, is defined as biliary changes seen in association with cavernomatous transformation of the PV with associated portal hypertension. Most often these changes are asymptomatic and discovered on imaging, but can occasionally cause obstructive jaundice. It is thought to be caused by ischaemic duct injury or compression of the extrahepatic bile duct by adjacent varices.
EHPVO may be encountered at any age but is more often a disease of childhood. Portal cavernoma is a major cause of portal hypertension in children and may account for as many as 30% of all children with bleeding oesophageal varices. Haemorrhage is common, but some children may present with asymptomatic splenomegaly. Umbilical vein catheterization in the neonate is a frequent cause, especially when catheter use is prolonged. Umbilical vein infection may induce fibrosis so that the PV fails to enlarge as the body grows. Conversely, congenital abnormalities, in particular atrial septal defects, malformations of the biliary tract and anomalous inferior vena cava, have been observed in association with EHPVO in children. Several cases of cavernous transformation have also been found associated with congenital hepatic fibrosis.
In adults, multiple risk factors are often present, but the major risks are hypercoagulable state, local or systemic infection or inflammation, vascular traumatic injury and congenital cardiovascular malformations ( Table 11.1 ). Hypercoagulable states include pregnancy, myeloproliferative disorders, JAK2 V617F mutation, Leiden factor V mutation, prothrombin factor II mutation, protein C deficiency, protein S deficiency, lupus anticoagulant or cardiolipin antibodies, homocysteine deficiency and homocystinaemia. Pylephlebitis, a septic thrombophlebitis of the portal venous system, is another risk factor for EHPVO and may be secondary to appendicitis, diverticulitis or omphalitis. Segmental PVT is common during acute cholecystitis. Surgical manipulations associated with EHPVO include laparoscopic surgery for various procedures, islet cell infusion in PV and liver transplantation (LT). Split-liver grafts have increased risk for PVT.
|Hypercoagulable states |
Inflammation and infection
Stasis and low portal blood flow
Primary antibody-deficiency syndrome
In some cases, no predisposing factors can be identified. With greater recognition of latent myeloproliferative disorders, however, only about 10–15% of cases are currently considered idiopathic.
Cirrhosis is one of the most common causes of PVT (see later Vascular lesions in cirrhosis ). By definition, cirrhosis is not included in the spectrum of EHPVO. Stasis and low portal blood flow seem to be the most important risk factor for PVT in cirrhosis. The 5-year cumulative incidence of PVT was 10.7% in a large recent series of patients with cirrhosis. Incidence of PVT increases with increasing severity of liver disease. Evidence of PVT was found in 5–36% of cirrhotic livers removed at transplantation. It is also a risk factor for poor early outcomes after LT.
PVT may occur in the context of liver malignancy. It is present in 10–40% of patients with HCC at diagnosis, and it is an adverse prognostic factor. PV obstruction also occurs in 5–8% of patients with metastatic tumour in the liver.
Histologically, in EHPVO, liver parenchyma is frequently unremarkable or shows only mild fibrosis. Autopsy or surgical specimens may sample large PVs and thus contain the obstructive lesions. The most obvious is phlebosclerosis with fibrous thickening of the intima and media, often associated with prominent increase of elastic fibres. Another finding could be the formation of thin webs, some of which can traverse the PV ( Fig. 11.3 ). Thrombosis and sometimes recanalization with multiple neovessels within fibrous obliterative tissue may be visible. In cases of extensive thrombosis, smaller or even distal PVs may be obliterated by the thrombus and replaced by fibrous tissue showing the typical feature of obstructive portal venopathy or hepatoportal sclerosis. When concurrent arterial hypoperfusion is present, acute PV obstruction can produce well-defined zones of hepatocyte atrophy. Rarely, true infarction can also develop. Persistent occlusion can lead to generalized or segmental atrophy of the liver, with the left lobe being particularly susceptible (see later discussion). Intense inflammatory infiltrates containing neutrophils can accumulate in the portal tracts and invade the PV walls, often with accompanying thrombosis, so-called pylephlebitis, or suppurative thrombophlebitis.
Congenital anomalies and portosystemic shunts
Congenital anomalies of the portal vein include agenesis, atresia and hypoplasia of the portal vein. Such anomalies may involve the entire length of the vessel or may be restricted to the point of entrance into the liver or just proximal to the division into two branches. These may be developmental or secondary to neonatal disease (see previous section). Portal vein aneurysm is a rare congenital anomaly or response to portal hypertension, usually occurring in the extrahepatic vein. Anomalous pulmonary venous drainage into a portal or hepatic vein has been reported, usually in association with cardiac and other anomalies.
Portosystemic shunts are abnormal blood vessels that divert a portion or all of the hepatic portal blood into the systemic venous system. Consequently, the diverted blood does not pass through the liver sinusoids. Congenital portal-systemic shunts may be intra- or extrahepatic and can lead to hepatic hypergalactosaemia, hepatopulmonary syndrome and encephalopathy. They can arise de novo, in response to cirrhosis and other obstructing lesions, or as a result of iatrogenic intervention (Fontan intervention). These shunts typically connect the PV with renal, adrenal or paraumbilical veins. Shunts may in turn lead to aneurysmal dilation of the PV and pulsatile retrograde PV blood flow, as well as secondary PVT and other ischaemic events.
Congenital absence of portal vein may be associated with congenital extrahepatic portosystemic shunts ( Abernethy malformation ). Histological examination of portal tracts in some of these patients may demonstrate abnormally formed vein ‘remnants’ ( Fig. 11.4 ). Two major subtypes of Abernethy malformation have been described. Type 1 consists of complete diversion of portal blood flow to a systemic vein, usually the vena cava; there are two subtypes. Type 1a occurs mostly in girls, has an absent PV, and the superior mesenteric and splenic veins enter other systemic veins separately. Type 1a is associated with cardiac or other congenital anomalies, including biliary atresia, polysplenia, situs inversus and oculoauriculovertebral dysplasia (Goldenhar syndrome). Type 1b occurs more frequently in boys and involves the area where the splenic and superior mesenteric veins join to form a PV before draining into a systemic vein. Type 2 Abernethy malformation consists of side-to-side portosystemic shunt, resulting in partial diversion. Type 2a is a congenital type usually occurring in boys and may be the equivalent of persistent ductus venosus. Type 2b is an acquired lesion usually caused by trauma or induced by portal hypertension. Of note, patients with absence of PV blood supply are prone to developing liver masses of various types, including focal nodular hyperplasia, liver adenomatosis, HCC and hepatoblastoma.
Intrahepatic portal vein lesions
Obstruction confined to the small PVs is probably an underdiagnosed cause of noncirrhotic portal hypertension. This group of diseases should be regarded as the intrahepatic variant (IHPVO) of EHPVO. The mechanism is thought to involve distal venous thrombosis as a result of a primary process localized to the small vessels or through spread from extrahepatic portal thrombi that subsequently undergo dissolution. Such proximal thrombosis is, in fact, identified in occasional cases. As previously mentioned, a sharp delineation between EHPVO and IHPVO is somewhat artificial since extrahepatic and intrahepatic PVT might be associated, and both are related to, similar aetiological factors (see Table 11.1 ). Nevertheless, several characteristic histopathological features of so-called hepatoportal sclerosis or obliterative portal venopathy have been reported, mainly in the context of intrahepatic disease, and are thus easily accessible to liver biopsy.
Obliterative portal venopathy/hepatoportal sclerosis
Obliterative portal venopathy (OPV) or hepatoportal sclerosis (HPS) has been reported worldwide, although more often from developing countries, where it is most frequently encountered in young men in the third to fourth decade of life. In contrast, in Japan and the West, there is a female preponderance and a tendency to present around the fifth decade. Whereas OPV usually presents with signs and complications of portal hypertension at diagnosis, similar histological lesions have been reported in a substantial proportion of patients without portal hypertension, which may represent early disease. Routine liver tests are usually normal or only mildly elevated. The hepatic venous pressure gradient is typically not significantly elevated. Although the natural history is not well defined, the disease is generally static or progresses only slowly. OPV does not evolve to cirrhosis, although hepatic failure has been noted as a terminal complication in some patients. With appropriate management of the portal hypertension, the overall prognosis is good.
Liver biopsy is essential to exclude cirrhosis or other causes of portal hypertension and to identify the discrete characteristic lesions. Indeed, the histological abnormalities of OPV/HPS have been recently reviewed in several studies. Unfortunately, the histological diagnosis of OPV is not always straightforward because lesions are unevenly distributed, as shown on pathological examination of explanted liver, and not all abnormalities are necessarily present in a single specimen. The key feature is phlebosclerosis, characterized by fibrous thickening and occlusion of the distal intrahepatic PVs within portal tracts ( Fig. 11.5 ). The affected vessels may be of any size, including the major right and left PVs, medium-sized veins of various order or small terminal PVs. The extrahepatic PV usually remains patent. The walls of the involved vessels are thickened, either concentrically or eccentrically, by connective tissue. Recent or past thromboemboli, with or without recanalization, can be detected in large portal tracts ( Fig. 11.6 ). Proliferation of neovessels in portal tracts with an increase in the total number of thin-walled vascular channels is another common feature ( Fig. 11.7 ). With severe involvement, the vein completely disappears, leaving only a fibrous scar. Preserved PVs may show thickened vascular walls with a conspicuous muscular layer even in the most distal PVs, indicating their exposure to elevated portal pressure ( Fig. 11.8 ). The phlebosclerotic lesions are irregularly distributed across the liver and vary greatly in their severity and extent. Those PV radicles that are unaffected by phlebosclerosis are frequently dilated and often ‘herniate’ outside the portal tract into the adjacent parenchyma, providing an ‘ectopic’ appearance ( Fig. 11.9 ). In some cases the vascular changes are accompanied by portal and periportal fibrosis of varying extent, with slender portal-based fibrous septa demarcating the liver parenchyma into inconspicuous nodules. Such a lesion may be difficult to separate from the so-called incomplete septal cirrhosis, which may represent an advanced-stage of chronic liver diseases ( Fig. 11.10 ) (see Vascular lesions in cirrhosis ). In cases without conspicuous phlebosclerosis, this fibrosis can be the dominant or the sole histological finding.
A variety of lobular alterations may also be noted. Perturbation in the lobular architecture leading to distortion of the normal relationship between the portal and central areas is common. The portal tracts are either abnormally approximated to each other or widely separated. The terminal hepatic veins may be increased in number or eccentrically located in the lobule adjacent to a portal tract in the periportal zone ( Fig. 11.11 ). Dilated, thin-walled sinusoidal structures are occasionally found adjoining the portal tracts (paraportal shunting) ( Fig. 11.12 ). Sinusoidal dilation is a frequent pattern in OPV, sometimes with perisinusoidal fibrosis and sinusoidal capillarization, as shown by aberrant expression of CD34. Sinusoidal lesions can vary in appearance but include widely dilated sinusoids in contact with atrophic hepatocytic cell plates. The sinusoidal lesions, as well as paraportal shunting, might represent pressure-related morphological signs of portal hypertension.
In addition, the hepatocytes may undergo nodular regenerative hyperplasia (NRH), producing poorly defined zones with widened hepatic plates alternating with localized parenchymal compression (see later discussion). Nodules of regenerative foci are separated by regions of hepatocellular/plate atrophy with condensation of reticulin fibres but without fibrous septation. Indeed, NRH has been proposed to result from obliteration of small portal venules, and the two disorders (NRH and OPV) may therefore form a pathological continuum. NRH may reflect a more advanced stage of the same disease. 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. The cut surface may show portal and perivascular fibrosis, dilation and thickening of vein walls. Partial nodular transformation, in which visible nodules of hyperplastic hepatocytes are located in the perihilar region of the liver, is another gross appearance. In some cases the biopsy specimens exhibit normal histology or mild portal fibrosis. Despite its nonspecificity, this observation can still be helpful in the setting of portal hypertension since it serves to eliminate cirrhosis and, by default, raise the possibility of OPV/HPS.
The pathogenesis of OPV has yet to be fully characterized, but a role of prothrombotic disorder is supported by studies from the West indicating association with prothrombotic states in 30–50% of the patients. Increased permeability in the intestinal barrier in the context of chronic GI inflammation may favour transmigration of bacterial products and may also play a role by causing inflammation and obliteration of small PVs. Such a mechanism might explain the association of OPV with coeliac disease and ulcerative colitis. Patients with human immunodeficiency virus (HIV) infection may have OPV/HPS, some with severe disease leading to LT. Nodular regeneration is more often observed in HIV-associated OPV. The pathogenesis has been related to either an acquired protein S deficiency or a drug-related vascular injury. The role of exposure to medications or toxins has been also reported, including vinyl chloride monomer, arsenical compounds, copper sulphate, antiretroviral therapy and cytotoxic chemotherapeutic drugs such as thioguanine. OPV has also been described in primary antibody-deficiency syndrome, including common variable immunodeficiency and congenital X-linked agammaglobulinaemia.
Obliteration of small PVs may also occur early in the course of liver disease of a variety of aetiologies, including primary biliary cirrhosis/cholangitis or primary sclerosing cholangitis. These lesions may cause presinusoidal portal hypertension before the development of biliary-type cirrhosis and in the absence of cholestasis, thus supporting the hypothesis that inflammation in the portal area promotes OPV. Also, similar reports link OPV with other autoimmune disorders, including systemic lupus erythematosus, scleroderma, Sjögren syndrome, rheumatoid arthritis, autoimmune hepatitis and Felty syndrome. Other examples are thought to result from autoimmune-induced vascular damages. Congestive portal venous injury in congestive heart failure, hepatic vein thrombosis (Budd–Chiari syndrome) and cirrhosis of all aetiologies is also regularly associated with obstruction of small PVs (see later discussions). Lastly, familial aggregation of idiopathic noncirrhotic portal hypertension has been described in some families, with demonstration of mendelian inheritance, autosomal dominant transmission.
Schistosomiasis is the most common cause of noncirrhotic portal hypertension worldwide (see Chapter 7 ). Eggs may migrate through the portal blood flow until they are stopped at the level of the small PVs, where a granulomatous reaction and fibrous obliteration of the veins may develop. In more advanced lesions, dense fibrosis of the medium and large portal tracts may develop, giving the typical gross appearance of ‘pipestem fibrosis’.
Hepatic artery-related lesions
The liver is remarkably tolerant to anoxic injury because of its rich dual blood supply, derived from both the portal and the systemic vascular compartment. Both vascular systems are closely connected to maintain a constant blood flow and proficient oxygen extraction. Nonetheless, with massive and rapid-onset disruption of the blood flow to the liver, this protection can be overwhelmed, resulting in ischaemic liver disease.
Aberrant hepatic arteries occur in a significant proportion of individuals. The existence of an accessory right hepatic artery (arising from the left HA and passing behind the PV bifurcation) must be recognized and appropriately managed during split-liver transplantation, to ensure a complete vascular supply to both grafts. Aneurysm and rupture of an aberrant HA can occur rarely.
Acute hepatic ischaemic necrosis and hepatic infarction
Acute hepatic ischaemic necrosis, also known as ischaemic hepatitis, shock liver or hypoxic hepatitis, is an acute liver injury believed to result from a sudden, profound reduction in systemic blood flow as typically occurs in shock. ‘Ischaemic hepatitis’ was described as early as 1901 in a series of autopsies that revealed homogeneous hepatic necrosis distributed around the central veins. The term ‘hepatitis’ is somewhat of a misnomer because in this setting the injury is not mediated by an inflammatory process. Nevertheless, the profound elevation in aminotransferases (transaminases) is similar to that seen in acute hepatitis.
Ischaemic liver injury can be related to various underlying conditions, including left ventricular failure, severe hypovolemia, septic shock, massive pulmonary embolism, hyperpyrexia and heat stroke. However, systemic hypotension or shock alone did not lead to ischaemic liver lesions in any patient. Indeed, patients with severe ischaemic lesions often had associated severe underlying cardiac disease. This suggests that passive congestion of the liver may predispose the liver to hepatic injury induced by a hypotensive event.
So-called ischaemic hepatitis is recognized clinically by a marked elevation in serum transaminase levels in the absence of other causes and in an appropriate clinical setting. Severe cases can be complicated by fulminant hepatic failure. The outcome is driven by the severity of the underlying cardiovascular disease. Improvement of the haemodynamic status may result in a rapid, dramatic hepatic response with normalization of serum transaminase levels within several days, and complete recovery is the rule. The prognosis is poorer in patients with unresponsive cardiac disease.
Two major histological patterns of ischaemic liver disease can be distinguished, centrilobular ischaemic necrosis and hepatic infarction . The two represent the same basic pathophysiological process but differ in the extent and distribution of the hepatic damage. Since the centrilobular area is especially vulnerable to ischaemic injury because of its location at the distal end of afferent blood flow, systematic zone 3 necrosis is the most frequent pattern. The necrotic zone is characterized by coagulative liver cell necrosis and pyknotic or karyorrhectic nuclei ( Fig. 11.13 ). The lesion is typically sharply demarcated, with apoptotic bodies often prominent at the interface between healthy and necrotic hepatocytes. Often the sinusoidal cells remain uninvolved. In more severe cases the process may affect much of the lobule, sparing the portal tract and periportal regions. 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. Within several days, the necrotic zone is infiltrated by a sparse inflammatory infiltrate of neutrophils and mononuclear cells, as well as variable numbers of pigmented macrophages. The apoptotic hepatocytes vanish, and the reticulin framework collapses. Sinusoidal dilation and congestion can be prominent if a component of right-sided heart failure is also present. Eventually, hepatocytic 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 with concurrent uraemia or hypercalcaemia.
The differential diagnosis includes other causes of confluent centrilobular necrosis, mainly toxicity of paracetamol (acetaminophen) or cocaine. Lesions caused by drug toxicity can be indistinguishable from shock-induced necrosis, given that severe toxic hepatitis may be associated with multivisceral deficiency and hypovolemic shock. Hepatitis related to herpesvirus infection also produces well-demarcated regions of necrosis. However, the margins of necrosis do not follow the hepatic acinar landmarks, and viral inclusions are often visible.
Other patterns of ischaemic hepatic necrosis without the typical zonation may be encountered. Periportal or irregularly distributed ischaemic necrosis can be observed in disseminated intravascular coagulation, toxaemia of pregnancy and HELLP syndrome (haemolysis, elevated liver enzymes, low platelet count). In these conditions, fibrin deposits may be found in sinusoids (zone 1), small PVs and arterioles.
Larger regions of necrosis involving multiple acini are recognized as hepatic infarcts. Hepatic infarcts are uncommon lesions, mainly recognized in autopsies. Large infarcts occur with combined portal and hepatic vein thrombosis, combined HA and PV thrombosis, or even in the absence of identifiable vascular thrombosis. Various causal factors leading to hepatic infarction have been reported, including those leading to arterial thrombosis (see later).
Grossly, an infarct of the liver appears as a peripherally located, wedge-shaped, yellow area of variable size, sharply demarcated with surrounding hyperaemia ( Fig. 11.14 ). However, it may be centrally located or may display a more irregular shape. The histological 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. After a few days, an acute inflammatory response becomes apparent at the border. If the patient survives, the final result is often a retracted fibrous to fibroelastic scar and/or segmental atrophy.
Late-stage (or chronic) severe ischaemic injury is often seen as a subcapsular lesion known as segmental atrophy . It can be mistaken for a ‘mass lesion’, so segmental atrophy may be biopsied at surgery. The findings may be variable, depending on whether the lesion is ‘early’ or ‘late’. The early lesions consist of collapsed or atrophic hepatic lobular parenchyma with preserved portal zones, irregular lobules or islands of hepatocytes, often with irregular patterns of fibrosis within the zone of ischaemia, and well-developed bile ductular reaction, with only mild elastosis. More advanced lesions contain much more elastosis, no ductular reaction and scant hepatocytic remnants ( Fig. 11.15 ). End-stage lesions can be extensively elastotic and may have the gross appearance of a nodule. Essentially all the cases of segmental atrophy, however, will contain abnormally thick-walled and often thrombosed vessels, with both arteries and veins involved, supporting these lesions as end-stage ischaemic events.
One of the more recently observed causes of hepatic infarction is the increased use of transcatheter arterial chemoembolization (TACE) for the ablation of liver tumours, particularly in the patient with end-stage liver disease in whom tumour resection is contraindicated, or when tumour needs to be ablated before LT. In these cases, in addition to necrosis of the tumour, adjacent parenchyma may also undergo ischaemic injury to a variable degree, especially in end-stage cirrhotic livers. For the latter, this can vary from outright necrosis to milder forms of injury, such as ductular transformation, or ‘metaplasia’, of cirrhotic nodules, where one sees variable degrees of replacement of hepatocytes by ductular structures within the confines of a nodule. One can also often see foreign body and granulomatous reaction in portal areas, as well as evidence of bile duct ischaemic damage, including bile extravasation.
Hepatic artery obstruction and ischaemic cholangiopathy
Hepatic artery thrombosis or obstruction is infrequent and caused by various acute or chronic local causes or diffuse disease ( Table 11.2 ). HA thrombosis may complicate abdominal trauma, vascular injury during liver surgery or laparoscopic cholecystectomy, the immediate post-transplant setting, transjugular intrahepatic portosystemic shunt (TIPS) insertion, arterial infusions, TACE, radiofrequency ablation of HCCs, arterial spasm after cocaine use, sickle cell crisis, HELLP syndrome, antiphospholipid coagulants and arteritis. The consequences vary greatly, the most common being ischaemic bile duct lesion (ischaemic cholangiopathy) and hepatic infarction (see earlier discussion).
|Local injury |
Ischaemic cholangiopathy is damage to bile ducts caused by restricted arterial blood flow. Indeed, bile ducts depend exclusively on arterial supply through a rich peribiliary vascular plexus. Therefore, HA occlusion may lead to biliary ischaemia. It is most often encountered in the post-LT setting, after inadvertent HA ligation mainly during liver surgery, after arterial catheterization for injection of alcohol or chemotherapeutic agents, after abdominal irradiation, with lupus anticoagulant, in polyarteritis nodosa and in paroxysmal nocturnal haemoglobinuria.
Ischaemic cholangiopathy is characterized by bile duct cell injury with pyknotic nuclei, cytoplasmic vacuolization and/or luminal desquamation of bile duct cells. Advanced lesions may lead to complete necrosis of the biliary tree with cholestasis, bile leak, stricture, cysts, rupture and necrosis of perihilar parenchyma ( Fig. 11.16 ).
Obliterative arterial changes, including subintimal foam cells and fibrointimal proliferation, are characteristic features of chronic allograft rejection (see Chapter 14 ). Because these alterations primarily affect the larger vessels and are segmentally distributed, they are often not demonstrated in biopsy specimens.
Chronic obliterative arterial changes can also be seen in chronic inflammatory diseases of the liver, with or without the background of cirrhosis (see later discussion). In livers without cirrhosis, variable changes involving both arteries and veins may be present in many types of chronic inflammatory conditions, similar to that seen in other body sites. These changes include variable degrees of intimal and medial fibrosis, possible increase in elastosis in and around the vessel, disruption or duplication of the elastic laminae ( Fig. 11.17 ) and possible mural calcification. Liver parenchyma near or peripheral to significant lesions may demonstrate atrophic changes, suggesting a possible ischaemic state, and medium to large bile ducts may show periductal fibrosis as a sign of ischaemic cholangiopathy (see earlier).
Arterial lesions in systemic disease
The arterial tree of the liver is frequently involved in patients with arterial disease elsewhere in the body as part of a systemic disorder (see also Chapter 15 ). The histological appearance of these lesions is the same as in other organs.
The liver may be involved in patients with most of the systemic arteritides, including polyarteritis nodosa, giant cell arteritis, Wegener granulomatosis, rheumatoid arthritis and drug-induced vasculitis. The histological appearance of these lesions is the same as in other organs ( Fig. 11.18 ). Lesions are usually clinically silent, although infarction or hepatic rupture can occur. Small-vessel arteritis may cause obliteration of adjacent PVs and lead to NRH and portal hypertension.
Small arterial branches can display the thickened, hyalinized walls of arteriolosclerosis as a feature of normal aging and systemic hypertension, although the liver is typically less affected than other organs. Atheromatous emboli may occur in patients with severe aortic atherosclerosis.
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 (see Chapter 15 ). Rare cases of intrahepatic arterial calcification have been described in idiopathic arterial calcification of infancy and hypercalcaemia caused by hyperparathyroidism.
Other arterial lesions
Hepatic artery aneurysms , although uncommon lesions, may be congenital or acquired after blunt trauma, percutaneous biliary drainage or even liver biopsy procedure. HA aneurysms may be intrahepatic or extrahepatic or associated with an aberrant artery and have a high risk of rupture, often with a poor outcome.
Aneurysms may also result in hepatoportal arteriovenous fistula or portobiliary fistula with secondary peritoneal haemorrhage or haemobilia. Small shunts from arterioles to hepatic or portal veins are widespread in cirrhotic livers. Congenital hepatoportal arteriovenous fistulae have been reported in infants.
The sinusoids are spaces directing blood from hepatic arteries and portal veins to the terminal hepatic venules. They provide an indispensible role in differentially supplying oxygenated blood and nutrients from the systemic circulation to the parenchymal cells throughout the hepatic acini. Proteins and metabolic products generated by hepatocytes are also transported through the sinusoidal spaces to the cardiac/systemic circulation. The space of Disse is a compartment between the sinusoidal spaces and the cytoplasmic membrane of hepatocytes without continuous basement membrane but wherein reticulin fibres are present. Hepatic stellate cells (HSCs) reside in the space of Disse and can transform into myofibroblasts when they are activated in chronic liver diseases. In normal liver the sinusoidal endothelial cells (SECs) are fenestrated and are immunohistochemically nonreactive to CD34 or CD31. In chronic liver injury the fenestration is decreased, and SECs become reactive to CD34 or CD31, starting in the periportal region and extending to the hepatic lobules. This phenomenon is called ‘capillarization of the sinusoids’. This process may be accompanied by activation of the HSCs in the space of Disse, which in turn leads to deposition of collagen in the sinusoidal spaces. SECs may also lack fenestrations and may be positive for CD34 in hepatocellular adenoma and HCC, and to a variable degree in some non-neoplastic conditions, such as cirrhosis of variable aetiologies, focal nodular hyperplasia and NRH. Although sinusoidal fibrosis is a common phenomenon in almost all chronic liver diseases, it is more apparent in nonalcoholic steatohepatitis, alcoholic liver disease, hepatic vein thrombosis (Budd–Chiari syndrome) and congestive hepatic fibrosis.
Dilation of the sinusoids occurs when there is focal obstruction of portal or hepatic veins with increased sinusoidal pressure. Therefore, outflow obstruction, increased portal pressure or increased arterial flow can all cause sinusoidal dilation. This change is often more apparent when accompanied by atrophy of the hepatocytes. Extravasation of red blood cells (RBCs) into the hepatic parenchyma, focal dropout of hepatocytes and accumulation of collagen fibres in the sinusoids are also common. Peliosis hepatis is a lesion of extreme sinusoidal dilation in which sinusoidal reticulin fibres are no longer intact (see next section).
Sinusoidal dilation is a nonspecific finding that often raises a differential diagnosis of outflow obstruction, including thrombosis of the hepatic vein (Budd–Chiari syndrome) and right-sided heart failure, and obstruction of the portal vein (discussed earlier). It may also be seen in nodules in liver cirrhosis, NRH, paraneoplastic phenomenon caused by renal cell carcinoma, wasting conditions (e.g. tuberculosis, HIV/AIDS), malignancy (e.g. Hodgkin lymphoma, carcinoma of stomach, uterus and colon), systemic inflammatory diseases (e.g. Crohn disease, Castleman disease, rheumatoid arthritis/Still disease, polymyalgia rheumatica) and sarcoidosis. Sickle cell disease can also cause remarkable sinusoidal dilation from the filling of the sinusoids with clumps of RBCs of sickle shape, accompanied by erythrophagocytosis and pericellular fibrosis. Some medications also cause sinusoidal dilation, such as azathioprine and oral contraceptives. Liver biopsies taken at abdominal surgery may demonstrate some degree of sinusoidal dilation; the mechanism for this is unclear but may result from alterations in portal blood flow during the procedure. Lastly, some causes of sinusoidal dilation may be mechanical or artefactual because of rough handling or stretching, so these types of changes may be more prevalent at the edges of the sample.
Peliosis can be found in the liver, spleen, bone marrow, lymph nodes, lungs and other organs. The term ‘peliosis’ derives from Greek pelios , which means dusky, black, blue or purple discoloration in gross appearance caused by extravasated blood. In peliosis hepatis, multiple blood-filled spaces ranging from several millimetres to 3 cm are randomly distributed throughout the liver. Microscopically, the cystically dilated spaces communicate with sinusoidal spaces, are filled with blood cells and are bordered by hepatocytes. Focal rupture of sinusoidal walls is suggested as its cause, which differs from sinusoidal dilation when the sinusoidal walls are intact. The rupture may be attributed to weakening of the fibres of the sinusoidal wall or to focal necrosis of the hepatocytes. Often, there is a lack of endothelial lining, but focal areas may be lined by endothelial cells, which most likely reflects a remnant of the original sinusoidal lining. Alternatively, re-endothelialization may also occur; thus the distinction between peliosis hepatis and sinusoidal dilation based on the presence or absence of sinusoidal endothelium may not be reliable. The lesions are randomly distributed without zonal preference.
Peliosis hepatis can been associated with cholestasis, liver failure and portal hypertension, although these may be caused by other, coexisting but undocumented vascular lesions rather than the peliosis per se . Peliotic lesions have a risk of rupture in relation to greater size of the spaces, and the rupture can be spontaneous or can follow trauma.
Conditions associated with peliosis hepatis include an array of chronic diseases, such as tuberculosis, leprosy, HIV/AIDS (see bacillary angiomatosis later), hairy cell leukaemia (thought to result from injury of sinusoidal wall induced by the leukaemic cells), vasculitis and malnutrition. Other associated conditions include LT and administration of agents such as 6-thioguanine, cyclosporine, azathioprine, thorium dioxide (Thorotrast), corticosteroids, anabolic steroids, tamoxifen, oestrogen, oral contraceptives and androgen. Subtler forms of peliosis hepatis are also observed in a variety of haematological disorders, including myeloproliferative diseases, Hodgkin lymphoma and Waldenström macroglobulinaemia with light-chain deposition.
Other peliotic-like lesions
Of note, peliotic change can be seen within neoplastic tissue per se , including HCC, in which immunohistochemical (IHC) stain for CD34 shows no positive cells along the spaces of peliotic change. The change may be associated with larger size of the tumour. Angiosarcoma may also show peliotic change, with malignant endothelial cells lining the cystic cavity.
Lipopeliosis is a rare liver lesion in which sinusoids appear to be engorged by fat droplets, reflecting the fat exiting the fatty hepatocytes that have dropped out because of necrosis and then have become entrapped within the space of Disse, with the appearance of entrapment in the sinusoidal spaces ( Fig. 11.19 ). Lipopeliosis has been associated most often with a lesion occurring in newly transplanted donor-liver allografts, with varying degrees of fatty change undergoing ischaemic and preservation injury. Its clinical outcome may vary greatly, depending on the extent of hepatocellular necrosis.
Bacillary angiomatosis, or bacillary peliosis hepatis, is a lesion caused by Bartonella spp. seen in patients with acquired immunodeficiency syndrome (AIDS) and other immunosuppressed patients. The clumps of organisms can be highlighted by a Warthin–Starry stain (see Chapter 7 ). Diagnosis can be confirmed by serology, culture and polymerase chain reaction (PCR) of peripheral blood or liver tissue. Bacillary angiomatosis is characterized by foci of peliotic-like change with hepatocellular necrosis, with multiple cystic blood-filled spaces. Peliosis of the lymph nodes and spleen and cutaneous angiomatous lesions may also be seen in these patients.
Sinusoidal obstruction syndrome (veno-occlusive disease)
Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is mostly seen in the setting of haematopoietic stem cell transplantation (HSCT; bone marrow transplantation, BMT), when myeloablative regimens are administered. Historically, its reported incidence ranges from approximately 5% to 60%, depending on the intensity of the conditioning regimen, type of transplant, presence of risk factors and diagnostic criteria used. In the early era of BMT, occurrence of SOS was reported to range from 21–25% in allogeneic graft recipients to 5% in autologous marrow recipients. More recently, the incidence has decreased significantly because of the better induction regimens and agents, but it has not been entirely eliminated. SOS also occurs when only radiation and chemotherapeutic agents are administered without BMT, supporting that this lesion results from injuries caused by radiation and toxic injury.
SOS is also known to occur in other settings, such as with ingestion of pyrrolizidine alkaloids, derived mostly from Senecio, Crotalaria , Heliotropium lasiocarpum or Symphytum spp. (the latter found in comfrey herbal tea). This condition is known as Senecio disease, Pictou cattle disease or heliotrope toxicosis. SOS can be caused by pyrrolizidine alkaloids found in herbal teas or contaminated grain, the latter leading to epidemics. These pyrrolizidine alkaloids have been documented in more than 150 species of plants, but several thousand potentially toxic species also exist (see Chapter 12 ).
SOS has also been observed in the use of oxaliplatin-based adjuvant or neoadjuvant regimens to treat patients with metastatic colorectal cancer of the liver. The underlying mechanism may be similar to that in BMT or HSCT patients, thought to be toxic injury to the SECs. Mice treated with oxaliplatin-containing regimens (FOLFOX) have shown liver pathology resembling SOS. In this model it appears that FOLFOX induces endothelial damage and leads to a prothrombotic state within the liver that may contribute to liver injury. Involvement of angiogenesis and coagulation pathways in sinusoidal injuries induced by oxaliplatin has also been suggested by molecular signatures.
SOS typically occurs in the paediatric population, although adults can also be affected. The onset may be acute or insidious. Acute disease is characterized by rapid onset of abdominal pain, hepatomegaly and ascites. Chronic disease may be histologically indistinguishable from cirrhosis of other aetiologies, with clinical features of portal hypertension or hepatic failure. Symptomatic SOS occurs in 50–60% of patients, with a mortality rate of 25%, clinically manifested as jaundice, weight gain, thrombocytopenia and liver failure with elevated transaminases and alkaline phosphatase within 3 weeks after treatment. Ascites and peripheral oedema may occur in up to one-quarter and two-thirds of patients, respectively.
The lesions of SOS are characterized by the presence of prominent obstructive, nonthrombotic lesions of the small hepatic veins in individuals exposed to intense chemical or radiation injury before BMT or HSCT, which must be distinguished from Budd–Chiari syndrome and Banti syndrome, the latter caused by different mechanisms of injury. In SOS the SECs are activated and damaged by the chemo- or radiotherapy conditioning regimens during BMT or HSCT. Initially, the insults lead to activation of the SECs, and subsequent damage ensues if the insults persist and intensify. The damage leads to the ‘rounding up’ of SECs, causing gaps in the sinusoidal barrier, such that leukocytes, RBCs and cell debris leak into the space of Disse and dissect, or disrupt, the continuous endothelial lining. These changes also separate endothelial cells from the underlying hepatocytes and allow blood flow into the hepatic parenchyma. Haemorrhage, congestion, hepatocellular necrosis and accumulation of haemosiderin-laden macrophages in zone 3, as well as subintimal oedema affecting the sinusoids and small hepatic veins, are manifested as early lesions ( Fig. 11.20 A and B ). The majority of the involved veins are small in calibre, with a diameter <300 µm. In the acute phase, thrombosis is not typically observed; however, deposition of fibrin may be recognized by IHC stains or electron microscopy. There may be only congestion and cholestasis in zone 3 in mild cases, whereas hepatocellular necrosis may be seen in severe cases. Over time the sinusoidal spaces are filled with extensive debris and thrombi composed of RBCs, sloughed SECs and white blood cells. HSCs are also activated during this process, which is thought to result in or enhance the deposition of collagen fibres in the sinusoidal spaces and hepatic venules, leading to sinusoidal fibrosis in zone 3 and fibrous obliteration of the small hepatic venules ( Fig. 11.20 C and D ), with concentric or eccentric intimal fibrosis and occasionally the formation of multiple venous lumina. Such venous lesions constitute the injury pattern of veno-occlusive disease; however, venous lesions are not always present on a needle biopsy, and congestion of sinusoids may be the only change observed.
Congestion of sinusoids in SOS raises a differential diagnosis of venous outflow obstruction, including congestive heart failure, constrictive pericarditis and thrombosis of the hepatic vein, or Budd–Chiari syndrome (BCS). In SOS, because of the extensive sinusoidal injury, a phenomenon of secondary thrombosis may occur affecting the large hepatic veins, with the end result resembling BCS. In comparison, BCS typically shows congestion and parenchymal destruction in zone 3, as in SOS, but does not demonstrate occlusion of the smaller terminal hepatic veins and venules. On the other hand, thrombosis of the large hepatic veins in BCS may be associated with fibrous obliteration of small hepatic veins that mimics SOS. Fibrous obliteration of small hepatic veins can also be seen in the advanced stages of nonalcoholic and alcoholic fatty liver disease. Neoplastic vascular invasion with luminal occlusion, such as that seen in epithelioid hemangioendothelioma (see Chapter 13 ), can give rise to clinical and histological features mimicking SOS. Therefore, clinical information is essential to facilitate establishing a definitive diagnosis.
Sinusoidal cellular infiltration
An abnormal cellular population, either neoplastic or non-neoplastic, may constitute infiltrates within the sinusoidal spaces ( Table 11.3 ). Lymphocytic infiltration within the sinusoidal spaces with ‘beads on a string’ pattern suggests Epstein–Barr virus (EBV) infection, also known as infectious mononucleosis (see Chapter 7 ). The differential diagnosis also includes hepatitis C virus (HCV) infection, malaria, autoimmune hepatitis and phenytoin toxicity. Lymphoma and leukaemic cells can frequently infiltrate sinusoids, but metastatic tumour cells from many sites may also infiltrate within the sinusoids as a less common phenomenon. Sickle-shaped RBCs in sinusoidal spaces are often observed in sickle cell disease. Extramedullary haematopoiesis in the sinusoids may be seen in myeloproliferative disorders or other diseases that invade and destroy the bone marrow. Nonhaematological neoplasia primary to the liver may also infiltrate the sinusoids, especially those of vascular origin, such as epithelioid haemangioendothelioma and angiosarcoma (see Chapter 13 ). Other cellular infiltration within the sinusoids includes rare disorders such as Rosai–Dorfman disease (sinus histiocytosis with massive lymphadenopathy), Langerhans cell histiocytosis and mastocytosis. IHC or special stains are often necessary to confirm the diagnosis in such cases.
|Sinusoidal dilation||Outflow obstruction|
|Increased portal pressure|
|Increased arterial flow|
|Paraneoplastic or neoplastic phenomenon|
|Wasting or infectious conditions|
|Peliosis hepatis||Injury and rupture of sinusoidal wall caused by weakening of fibres of sinusoidal wall or by focal necrosis of hepatocytes|
Drugs: 6-thioguanine, cyclosporine, azathioprine, Thorotrast, corticosteroids, anabolic steroids, tamoxifen, oestrogen, oral contraceptives, androgen
|Sinusoidal obstruction syndrome (veno-occlusive disease)||Injuries of sinusoidal endothelial cells by radiation and/or toxic injury||Haematopoietic stem cell transplantation (bone marrow transplantation)|
|Sinusoidal cellular infiltration||Lesional cells infiltrating in the sinusoids|
Amyloidosis and light-chain deposition disease
Hepatomegaly, cholestasis, portal hypertension, ascites and/or liver failure may be the clinical presentation in patients with amyloidosis involving the liver. These symptoms may be accompanied by clinical manifestations of systemic disease with involvement in other organs, such as cardiomyopathy, nephrotic syndrome and renal failure. Acellular and dense deposition of amyloid material along the perisinusoidal space is the characteristic finding. The hepatocellular cords may appear atrophic, and bile plugs may be noted between remaining hepatocytes. In addition to deposition within the sinusoidal spaces, amyloid may also deposit in the arterial wall, portal tracts or liver parenchyma, as well as in the subepithelial spaces of bile ducts and peribiliary glands. Overall, inflammation is typically unremarkable in hepatic amyloidosis, but ductular reaction may be present. Identical histological findings as just described can also be seen in light-chain deposition disease. Deposition of amyloid can be readily visualized on routine haematoxylin and eosin (H&E) stain and confirmed by a Congo red stain, showing the typical apple-green birefringence under polarized light. These entities are discussed further in Chapter 15 .
Hepatic vein lesions
Normal variations and congenital anomalies
Three hepatic veins (right, middle and left) drain from the upper part of the posterior surface of the liver into the inferior vena cava (IVC). These large veins exhibit considerable anatomical variation, which is of particular importance for liver surgery, especially living-related LT. Collateral drainage between anatomical segments is often sufficient to ameliorate the effects of hepatic vein obstruction. The hepatic venous drainage of the caudate lobe usually is directly into the IVC. In the past, membranous obstruction of the hepatic portion of the IVC, mostly reported from Asia and South Africa, was considered a congenital malformation associated with hepatic vein occlusion and increased risk for HCC. However, in the 1990s, convincing evidence of an acquired (thrombotic) aetiology was provided, supported by the common occurrence of infection (see next section).
Budd–Chiari syndrome (BCS) is an eponym for hepatic venous outflow obstruction, independent of the level or the mechanism of obstruction. Such obstruction may involve large hepatic veins, small hepatic veins and/or IVC and causes congestive hepatopathy. Cardiac and pericardial diseases as well as the sinusoidal obstruction syndrome are excluded from the definition of BCS. In Western countries, BCS is usually caused by hepatic vein obstruction, whereas in Asia, obstruction usually involves the IVC or both IVC and hepatic veins.
Aetiology and pathogenesis
BCS is classified as ‘primary’ when it is related mainly to venous disease, such as thrombosis or phlebitis, and ‘secondary’ when it is caused by venous compression or invasion by a lesion originating outside the veins, such as an abscess or a tumour. Many conditions have been reported to cause BCS ( Table 11.4 ). Similar to previous editions of this chapter authored by I.R. Wanless, these conditions have been divided into categories related to pathogenesis and include hypercoagulable states, stasis or mass lesions, vascular injury, surgical manipulation and uncertain mechanisms. Most patients in American, British and French series have a predisposing factor belonging to Virchow triad.
|Hypercoagulable states |
Stasis or mass lesions
Surgical manipulation-related stasis or injury
Associations of uncertain mechanism
In most reported cases, primary BCS is the result of prothrombotic conditions, which are often unknown at clinical presentation. A recent multicenter study found that 86% of 163 patients had at least one thrombotic risk factor, and 46% had more than one. Myeloproliferative disorders (e.g. polycythaemia vera, essential thrombocythaemia), inherited thrombophilic conditions (e.g. factor V Leiden G1691A mutation), antiphospholipid antibodies, hyperhomocysteinaemia, paroxysmal nocturnal haemoglobinuria and oral contraceptive use have been identified as the most common risk factors of primary BCS. Detection of the Janus kinase 2 (JAK2)-activating V617F mutation has recently emerged as a sensitive marker to reveal myeloproliferative disorders underlying BCS. In contrast to portal vein thrombosis (PVT), the local factors determining the development of venous outflow thrombosis remain unknown in the majority of patients.
Environmental conditions and infection appear to play significant roles in hepatic venous outflow obstruction occurring in developing countries. Okuda et al. have drawn attention to the relatively common occurrence of membranous obstruction of the hepatic portion of the IVC in the developing world. Originally thought to represent a congenital malformation, this membranous lesion is now considered to be the remnant of organized and recanalized thrombus. Various neoplasms cause secondary BCS ( Table 11.4 ). In an autopsy study from Japan, invasion of one or more of the three hepatic veins was found in 23% of 232 patients with HCC; this was usually accompanied by PVT.
Clinical features, diagnosis and treatment
BCS occurs over a wide age range. In a recent series of 163 patients, median age at diagnosis was 38 years, and 57% of patients were female. The clinical presentation depends on the speed and extent of venous outflow obstruction and varies broadly from absence of symptoms to fulminant hepatic failure, with most cases showing either a rapid (‘acute’) or more often a progressive (‘chronic’) development of symptoms over weeks to months. Acute obstruction of all three hepatic veins typically causes abdominal pain, hepatomegaly, ascites and liver dysfunction, demonstrated with elevated serum transaminases and decreased coagulation factors. Fever and hepatic encephalopathy may also be part of the clinical presentation. Cases with progressive (chronic) development of symptoms are characterized by indolent development of ascites, splenomegaly or portal hypertensive bleeding, as well as mildly to moderately abnormal liver function tests (LFTs). Some suggest that an ‘acute on chronic’ manifestation has a worse outcome than an acute or a chronic manifestation alone. Obstruction of only one or two of the hepatic veins may manifest with hepatomegaly and mild or transient changes of LFTs. On the other hand, obstruction of the IVC can cause marked dilation of subcutaneous veins of the trunk, as well as oedema of the lower extremities. Up to 20% of patients with BCS are asymptomatic; the lack of symptoms has been associated with large intrahepatic and portosystemic collaterals.
Noninvasive hepatic imaging is the mainstay for diagnosis of BCS, including Doppler-ultrasonography (US), magnetic resonance imaging (MRI) and computed tomography (CT), often in combination. Direct x-ray venography, an invasive procedure, is useful to establish the diagnosis in difficult cases and precisely determine obstructive lesions before treatment. Ascitic fluid protein content higher than 3 g/dL is suggestive of BCS, provided cardiac and pericardial disease as well as SOS have been excluded. Liver biopsy is useful in difficult cases because it can provide indirect but strong evidence of venous outflow obstruction, exclude other conditions that may be part of the differential diagnosis, and provide clues to the aetiology of BCS, such as sarcoid granulomas, microorganisms and extramedullary haematopoiesis suggestive of a myeloproliferative disorder. The histological features of BCS may show significant regional or segmental variation within the liver ; therefore it is recommended not to use the liver biopsy for assessment of prognosis. Nevertheless, multiple biopsy specimens from different sites of the liver provide a better impression of the pathological changes than a single biopsy specimen.
Treatment of BCS includes specific therapy of the cause, if known; anticoagulation therapy; pharmacologic and endoscopic treatment of portal hypertension; recanalization of the hepatic venous outflow tract by thrombolysis, angioplasty or stenting; portosystemic shunting for liver decompression and LT. In the majority of patients the disease can be fully controlled, with survival >80% at 2 years. Adverse outcomes may be caused by underlying haematological disorders. There is also an increased risk for HCC in longstanding BCS, especially in cases with membranous obstruction of the IVC.
The gross and microscopic features of BCS are variable and depend on the location, severity and duration of hepatic venous outflow obstruction. Acute obstruction of the three hepatic veins causes hepatomegaly with dark-red discoloration and rounded edges ( Fig. 11.21 ). On the other hand, the gross appearance of livers chronically involved by BCS is characterized by atrophy of involved lobes and compensatory hyperplasia of unaffected regions, reflecting ongoing venous thrombosis, organization and recanalization of thrombi, and in some cases, superimposed thrombosis of PV branches. The cut surface of the liver shows areas of congestion, haemorrhage and fibrosis. A variegated, mottled appearance (‘nutmeg’ pattern) may be evident in some or most areas. Compensatory hyperplasia of the caudate lobe, caused by sparing of the corresponding veins which drain directly into the IVC is a characteristic gross feature of BCS.
In patients with acute presentation, microscopic examination shows marked congestion and dilation of centrilobular and midzonal sinusoids, extravasation of erythrocytes into the space of Disse and the liver cell plates, as well as hepatocyte necrosis of variable extent ( Fig. 11.22 ). Fresh and organizing thrombi may be seen in hepatic vein branches of any size. Linking of adjacent central veins with haemorrhage and necrosis is often found. Periportal regions are spared and demonstrate features of regeneration, such as thickened cell plates. The portal tracts lack significant pathological changes. Panlobular necrosis and haemorrhage may be seen in BCS, especially in areas with superimposed PVT.
Over time, the venous thrombi become organized and may recanalize, leaving intimal fibrosis (often in the form of multiple layers), delicate webs or multiple lumina. Affected parenchymal regions show fibrosis and obliteration of central veins/venules ( Fig. 11.23 ), centrilobular fibrosis, sinusoidal congestion/dilation and perisinusoidal fibrosis ( Fig. 11.24 A ). In addition, the hepatocytes in the most ischaemic zones become atrophic and/or drop out, and in some cases, these ‘atrophic hepatocytes’ may form ductular-like structures as a result of the chronic ischaemic injury; these structures can stain positively for keratin 7 (see Fig. 11.23 ).