Digestive and Liver Disease

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1 Digestive and Liver Disease 43 (2011) Contents lists available at ScienceDirect Digestive and Liver Disease journal homepage: Review article Vascular disorders of the liver: Recommendations from the Italian Association for the Study of the Liver (AISF) ad hoc committee Marco Senzolo a,1, Oliviero Riggio b,1, Massimo Primignani c,,1 a Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Italy b Gastroenterology II, Dept of Clcinical Medicine, Sapienza University of Rome, Italy c IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Gastroenterology and Endoscopy Unit, Milan, Italy article info abstract Article history: Received 26 July 2010 Accepted 23 November 2010 Available online 24 December 2010 Keywords: Vascular liver disorders Thrombosis Coagulation This review summarizes the document elaborated by the Italian Association for the Study of the Liver (AISF) ad hoc committee Vascular disorders of the liver on the primary circulatory liver diseases, which include Budd Chiari syndrome, obstruction of the hepatic portion of the inferior vena cava, portal vein thrombosis, sinusoidal obstruction syndrome (veno-occlusive disease) and hereditary hemorrhagic telangiectasia. A characteristic of the primary circulatory liver diseases is that portal hypertension usually precedes liver dysfunction. Significant overlap exists amongst the diseases and risk factors that predispose patients to the primary circulatory liver diseases, though the pathogenesis of individual diseases varies. Management of the different vascular disorders is very peculiar and often multidisciplinary and patients should be referred to a tertiary referral centre for optimal care Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Portal vein thrombosis/extrahepatic portal vein obstruction (EHVPO) 1.1. Introduction The term Portal vein thrombosis refers to the development of thrombosis within the extrahepatic portal venous system with possible extension downstream to the intrahepatic portal vein branches or upstream to the superior mesenteric and splenic veins. Since thrombosis is the main but not the only cause for portal vein obstruction, the more comprehensive term extraheaptic portal vein obstruction (EHPVO) should be preferred, particularly when the occlusion of the portal vein, owing to neoplastic invasion or compression, is not primarily thrombotic. The development of porto-portal collateral vessels at the liver hilum is defined as cavernous transformation of the portal vein. Although the development of such collaterals begins to occur early after a complete, unrelieved portal vein obstruction, the occurrence of a full blown cavernoma is regarded as the consequence of a chronic occlusion of the portal vein [1]. Due to relevant clinical and therapeutic implications, the definition of EHPVO should be augmented by statements referring to the extension to the superior mesenteric Corresponding author at: Via Francesco Sforza 35, Milan Italy. Tel.: ; fax: address: martin@policlinico.mi.it (M. Primignani). 1 On behalf of the Italian Association for the Study of the Liver (AISF) ad hoc committee Vascular disorders of the liver. (SMV) or splenic vein (SV), the coexistence of a portal cavernoma and the presence or absence of liver cirrhosis and abdominal neoplasm. The following recommendations apply only to EHPVO as a primary vascular disorder of the liver, not occurring as a complication of a pre-existing parenchimal liver disease or in the setting of abdominal cancer Aetiology and pathogenesis The pathogenic factors involved in EHPVO and other splanchnic vein thromboses do not differ from those long identified for venous thromboembolism: vessel wall damage, slowing of blood flow and hypercoagulability, i.e. a procoagulant imbalance due to increased plasma levels of coagulation factors caused by acquired disorders (amongst these are cancer and inflammation) or inherited thrombophilia [2]. EHPVO must be regarded as a multifactorial process in which both local and systemic factors concur. Besides malignancy (mostly hepatocellular carcinoma, pancreatic cancer and cholangiocarcinoma), local factors include abdominal inflammatory precipitating causes (mainly acute and chronic pancreatitis, diverticulitis, appendicitis, inflammatory bowel diseases and liver abscess) and abdominal surgery, particularly when injury to the portal venous system is involved. The coexistence of an abdominal neoplasm usually excludes the need for thrombophilia screening, given that recognition of latent thrombophilia would not modify treatment or clinical outcome. Conversely, EHPVO in the setting of a compressive inflammatory mass should /$ Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi: /j.dld

2 504 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) prompt the search for associated latent systemic prothrombotic conditions. EHPVO is an important complication of liver cirrhosis. Its reported incidence in compensated disease is between 0.6% and 5%, but becomes much higher (up to 25%) in advanced disease [3]. Slowing of portal flow [4] and a procoagulant imbalance mainly due to increased factor VIII levels and decreased levels of naturally occurring anticoagulants [5], are the causal factors involved. Thus, liver cirrhosis can be regarded as an acquired prothrombotic disorder. However, a concurrent role of inherited thrombophilia can be suspected when EHPVO occurs in the early compensated stages of cirrhosis. Indeed, in cirrhotic patients with EHPVO an increased prevalence of factor V Leiden and prothrombin gene mutations has been demonstrated. When hepatocellular carcinoma supervenes, the incidence of EHPVO further increases to about 40% [6]. The occurrence of EHPVO in the absence of pre-existing liver disease usually leads to mild consequences to liver function and a compensatory hypertrophy of the arterial vascular bed [7]. Within a few days, if the obstruction is not relieved, the development of porto-portal collaterals to compensate for the obstruction begins, leading in the long term to the formation of a full-blown portal cavernoma. However, despite this compensatory phenomenon enables a consistent amount of portal blood to reach the liver, it is not sufficient to avoid the development of presinusoidal portal hypertension and of oesophagastric varices. The frequent occurrence of ectopic varices in the duodenal or intestinal wall is quite peculiar of this condition [7,8]. In EHPVO one or more systemic prothrombotic factors can be identified in about 60% of patients, whereas local factors (often acting as precipitating factors) are present in up to 40% of patients [7 11]. However, when EHPVO is discovered at the chronic stage of portal cavernoma, the occurrence of a previous precipitating local factor is easily missed. Current aetiologic investigations fail to recognize the cause for EHPVO in about 20% of patients, thus suggesting the existence of still unidentified prothrombotic disorders. Moreover, causes of noncirrhotic portal hypertension should be screened, especially in those patients without evident risk factors for thrombosis [12]. Noninvasive tests such as fibroscan could perform in place of liver histology to screen for non-cirrhotic hepatic fibrosis. As for local risk factors, hormonal factors such as pregnancy, oral contraceptives or oestrogen substitutive therapy should be regarded as facilitating conditions in the setting of an underlying prothrombotic disorder, rather than risk factors per se [13] Clinical manifestations Clinical manifestation depends on the time of diagnosis. Whereas in the past EHPVO was most frequently diagnosed at the late stage of portal cavernoma, nowadays, with the current wide availability of imaging techniques, the diagnosis at the acute stage is achieved in more than 50% of cases [14]. The acute onset is with abdominal pain, often radiating to the back, fever (also in the absence of an underlying infection) and, less frequently, ascites. Rarely, gastrointestinal bleeding is the presenting symptom of acute EHPVO. A painful liver with spiking fever and chills is suggestive of septic portal vein thrombosis. Symptoms, however, can be negligible or completely lacking, particularly if the portal vein obstruction is partial. Biochemical signs include mild, transient elevation of serum aminotransferases and an increase of acute phase reactants. A high hematocrit level or platelet count suggests an underlying myeloproliferative disorder. When the obstruction extends to the mesenteric vein, particularly if the proximal small mesenteric vein arches are involved, symptoms are more severe, with colicky abdominal pain radiating to the back, ileus, hematochezia, ascites and metabolic acidosis. These features are suggestive of venous mesenteric ischemia or intestinal infarction [15]. The presence of portal hypertension with recurrent, usually well tolerated variceal bleeding episodes is the most typical manifestation of chronic EHVPO. Other clinical features include an enlarged spleen, thrombocytopenia and mild to severe cholestasis, suggestive of compression of the biliary tree exerted by the cavernoma (portal biliopathy) Diagnosis Disturbance of the portal vein flow, evidence of the thrombus or presence of portal cavernoma are the leading elements for diagnosis of EHPVO. Ultrasonography with Doppler is usually sufficient for diagnosis. Contrast enhanced computed tomography (CT) scanning and abdominal magnetic resonance imaging (MRI) are more adequate to assess the extension of the obstruction to the mesenteric vein and the occurrence of signs of bowel infarction, such as thinning or thickening of the intestinal wall, lack of mucosal enhancement after contrast injection or the presence of intramural gas. MRI allows the study of the biliary tree if portal biliopathy is suspected [16]. For the etiologic workup, a complete screening for thrombophilia should be always performed as described in Table Prognosis Recent series report 10% mortality at 5 years. Amelioration of prognosis in recent years is likely due to the early use of anticoagulation in the acute forms, and to the better management of portal hypertensive complications and of the underlying prothrombotic conditions [8]. Extension of the thrombus to the SMV and the mesenteric vein arches leading to mesenteric infarction is a dreadful condition leading to mortality in 25 50% of cases, despite prompt surgical resection of the necrotic bowel [15,17]. Established or chronic EHPVO most frequently presents with problems related to portal hypertension, mainly including gastrointestinal bleeding and hypersplenism. Mortality related to variceal bleeding is lower than in cirrhotic patients [18]. New thrombotic events due to underlying prothrombotic conditions occurs in 5/100 patients per year. Portal biliopathy, due to compression/ischaemia of the biliary tree occurs usually in the presence of portal cavernoma, but in most cases is asymptomatic. However, biliary complications such as cholecystitis, cholangitis or choledocolithiasis occur in about 5% of cases and may be severe and life-threatening. In patients with chronic myeloproliferative disorders, particularly idiopathic myelofibrosis and polycythemia vera, the prognosis is more related to the underlying haematologic disorder than to EHPVO Treatment Anticoagulation The aim of anticoagulant treatment is to promote portal vein repermeation and prevent extension of thrombosis to the SMV to avoid intestinal infarction. In acute EHPVO the early use of anticoagulation leads to repermeation and prevents the development of portal hypertension in more than 40% of cases [19]. Anticoagulation should be considered also in extensive thrombosis if recent (<6 months), since at least partial portal vein repermeation might be achieved and further progression avoided. Anticoagulation in acute forms should be performed with heparin, followed by warfarin when invasive procedures are no longer needed, targeting the INR at a 2 3 range. Low molecular weight heparins (LMWH)

3 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) Table 1 Recommended laboratory tests for thrombophilic factors in portal vein thrombosis. 1. Myeloproliferative disorders (MPD): CBC, bone marrow aspirate, JAK2 mutation 2. Factor mutations: Factor V Leiden, Prothrombin 3. Factor deficiency: Protein C, Protein S, Anti-thrombin 4. Anti-phospholipid antibody: Anti-cardiolipin, Lupus anti-coagulant, Anti-b2-glycoprotein I 5. Paroxysmal nocturnal hemoglobinuria: Flow cytometry for CD55- and CD59 deficiency 6. Hyperhomocysteinemia: Folate, vitamin B12, and homocysteine; MTHFR polymorphism are currently preferred, since they are as effective as unfractioned intravenous heparin, have a more predictable dose response relationship and do not require laboratory monitoring. Furthermore, LMWH carries a lower risk of heparin induced thrombocytopenia (HIT) as compared to unfractioned heparin. Anti-Xa levels should be monitored in severely obese or pregnant patients and in presence of renal insufficiency. Follow-up of patients undergoing anticoagulation can be performed with doppler ultrasound at 1, 3 and every 6 months. Repermeation of the portal vein has never been shown to occur after the first 6 month of treatment. Hence anticoagulation should be carried out for at least 6 months. However, long term anticoagulation is currently recommended, irrespectively of the achievement of portal vein repermeation, in the presence of thrombophilia, or a personal or familial history of thrombosis or in the case of intestinal ischemia to prevent the risk of further progression. Negative predictive factors for repermeation are a long time elapsed between EHPVO onset and the start of anticoagulation treatment, ascites at baseline, whether clinically detectable or at imaging, and co-existence of splenic vein thrombosis [19]. In chronic EHPVO, the use of anticoagulation is controversial, given the risk of portal hypertension-related bleeding. However, provided that prophylactic measures to prevent bleeding are adopted (i.e. beta-blockers and/or banding ligation) and effective, these patients may be treated with anticoagulants, particularly in the case of a persistent prothrombotic condition carrying the risk of thrombosis recurrence or progression [20] Other treatments for acute EHPVO Indeed, about two thirds of patients with ascites at presentation will not achieve portal repermeation despite early anticoagulation [19] and could be selected for more aggressive treatment, other than anticoagulation, such as thrombectomy, local or systemic thrombolysis, balloon angioplasty or stent placement, or a combination of these procedures. Unfortunately, recurrence of thrombosis after surgical thrombectomy is usual, unless anticoagulation is not promptly applied. Thus, surgical thrombectomy is not indicated unless surgery is needed when intestinal infarction is suspected. As far as thrombolysis is concerned, the risks of severe adverse events should be considered. Therefore, thrombolysis should be limited to patients with severe or progressive disease unresponsive to anticoagulation. In general, the efficacy and the risk-benefit ratio of invasive treatments compared to anticoagulation should be evaluated in selected patients with extensive thrombosis of the portal venous system deemed unresponsive to anticoagulation alone Management of chronic EHPVO The management of portal hypertensive complications is similar to cirrhotic patients, although no randomized controlled trials (RCTs) have been performed in this clinical setting. If oesophageal varices at risk of bleeding are present when anticoagulation is recommended, prophylactic treatment with nonselective betablockers and/or endoscopic treatment (preferably banding) should be performed first. Issues can be raised for the use of vasoconstrictor agents during variceal bleeding in patients with EVPHO due to the risk of progression of thrombosis due to splanchnic vasoconstriction. However, there are no data to support this concern. Thrombolysis has been shown to be effective in some reports, alone or associated with transjugular intrahepatic porto-systemic shunt (TIPS) which can restore blood flow in the vessel and allow anticoagulation when contraindicated by high risk varices. TIPS should be considered when there is progression of PVT with or without intestinal ischaemia despite anticoagulation or when anticoagulation is contraindicated [21]. TIPS is also indicated in chronic EHVPO in case of failure in controlling variceal bleeding and in the endoscopic failures of symptomatic portal biliopathy. TIPS can be attempted even in presence of cavernomatous transformation when the intrahepatic branches of PV are patent [22]. Feasibility of TIPS in patients with portal vein thrombosis has been recently further confirmed in a cohort of 13 patients in which the procedure was successful in 83% [23]. No large prospective studies exist to evaluate prognosis in patients with TIPS in EHPVO. Decompressive surgery, mainly distal splenorenal shunt or H graft mesocaval shunts, should be considered in failures of endoscopic therapy for bleeding or biliary complications, particularly when a TIPS is not feasible. 2. Budd Chiari syndrome 2.1. Introduction The Budd Chiari syndrome (BCS) is caused by obstruction of hepatic venous outflow at any level from the small hepatic veins to the junction of the inferior vena cava (IVC) with the right atrium [24] in the absence of right heart failure or constrictive pericarditis. It occurs in 0.2 per million inhabitants per year with a prevalence ranging from 1/1,000,000 of the general population in Western countries to 1/100,000 in Nepal [25 27]. Obstruction of hepatic venous outflow is mainly caused by primary intravascular thrombosis, which sometimes occurs suddenly or repeatedly over time, accompanied by some revascularization accounting for the variable parenchymal hepatic damage and presentation Aetiology and pathogenesis At least one procoagulative disorder occurs in the vast majority of patients and almost half of patients have more than one underlying disorder [27]. This means that identification of one causal factor should not halt the search for other causes. Myeloproliferative disorders (MPD) are the main cause in 20 50% of patients [28] using standard diagnostic criteria, and up to 80% if spontaneous erythroid colony formation is diagnosed [29]. A recent advance on diagnosis has been made with the identification of a mutation in the Janus tyrosine kinase-2 (JAK2) gene in the myeloid cells [30]. JAK2 mutation has been detected in about 50 80% of patients with MPD and 37 45% of BCS patients and 80% of BCS patients with MPD. In the remaining patients bone marrow biopsy should be performed to exclude the diagnosis. Amongst other acquired thrombophylic conditions, Bechet s disease is the leading cause of BCS in the endemic areas. Paroxysmal nocturnal hemoglobinuria is an extremely rare disease with a severe prognosis and a close association with BCS. The incidence of BCS during the course of the disease is about 35%. Flow cytometry on peripheral blood for detection of the CD55 and CD59 deficient

4 506 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) clone is the current standard for diagnosis and should be carried on in any case of BCS [31]. Treatment therapies include monoclonal antibodies and bone marrow transplant. The diagnosis of antiphospholipid syndrome is difficult due to the rather high prevalence of anticardiolipin antibodies in chronic liver disease. Other thrombophilic disorders are seen as a cause of BCS in 20% of cases. The factor V Leiden mutation is commonly found [28] whereas the G20210A prothrombin gene mutation appears to be less over represented amongst BCS [2]. Diagnosing protein C protein, S or antithrombin deficiency is not straightforward as reduced concentrations can be caused by impaired hepatic synthesis. Given the rarity of these disorders, a true deficiency can be suspected when isolated, whereas decreased plasma levels of all these natural occurring anticoagulants clearly indicate an acquired impaired synthesis. However, a familial study, when feasible, is the only confirmatory test of true deficiency. Oral contraceptive use is a risk factor for BCS (particularly high oestrogen content pills), related to heterozygosity or homozygosity for thrombophilic defects, including ones as yet unknown [32]. BCS in pregnancy (usually postpartum) is associated with oestrogen changes, IVC compression and physiologic hyperfibrinogenemia. A summary of prevalence of BCS prothrombotic defects with suggested diagnostic panel is listed in Table Clinical manifestations BCS should be suspected in patients with acute abdominal pain, an enlarged liver particularly with known thrombophilia, or when fulminant liver failure is associated with ascites [32]. Chronic BCS should be excluded when there is refractory ascites, particularly if liver function tests are relatively normal [33]. Leg oedema and venous collaterals on the trunk indicate IVC compression/thrombosis [34]. Ascites chemistries frequently reveal a high serum-ascites albumin gradient and total protein above 25 g/l i.e., non-cirrhotic ascites. The severity of presentation has led to a traditional classification of fulminant associated with hepatic encephalopathy (5%), acute (20%) [35], subacute or chronic BCS (60%) [33] with proportions seen in reported series. However the prognostic value of this classification has not been prospectively validated and several authors no longer recommend it to predict mortality [36 38]. When there is concomitant PVT usually the presentation is more severe. Asymptomatic BCS appear to account for about 15% of cases [33] (no ascites or abdominal pain) and is usually diagnosed fortuitously, following investigation of slightly abnormal results in liver function tests. The absence of ascites is attributed to long-standing, venous collaterals connecting occluded and patent hepatic vein tracts. In acute BCS 58% of patients have histological evidence of chronic disease [39] as recent thromboses compound previous subclinical thromboses. Hepatocellular carcinoma appears to complicate BCS with an incidence similar to other chronic liver diseases. HCC developed in 11 of 97 patients in a recent cohort followed up for a mean of 5 years [40] and the incidence of HCC in patients with membranous IVC obstruction is reported to range from 25% to 47.5% [41] Staging the venous obstruction BCS is classified into four disease types according to the site of the venous obstruction and in addition to the presence or absence of portal vein thrombosis: hepatic vein obstruction/thrombosis without IVC obstruction/compression; hepatic vein obstruction/thrombosis with IVC obstruction (as a result of compensatory caudate lobe hypertrophy, or IVC thrombosis) [24]; isolated hepatic webs; isolated IVC webs. Portal vein thrombosis occurs in about 15% of patients with BCS in the largest series associated with the presence of multiple prothrombotic factors and is considered as a negative prognostic indicator associated with a mean survival of 1 month compared with 6.3 years without PVT [42]. Another study reported a 85% five year survival in non-pvt BCS patients versus 58% when PVT was present [35]. Medical or mechanical thrombectomy combined with TIPS is, however, changing this poor prognosis [43]. Primary membranous obstruction of the IVC is a consequence of thrombosis, occurring without hepatic vein thrombosis and accounts for 60% of BCS patients in Asia [23,37]. However this pattern has changed over time and IVC obstruction now accounts for lesser proportion of cases in India [44]. Diagnosis is based on the demonstration of an obstructed hepatic venous outflow tract. Colour and pulsed doppler ultrasound has a diagnostic sensitivity of almost 80% and is the recommended firstline investigation [45,46]. CT or MRI, in addition, show the typical diagnostic feature of patchy enhancement of hepatic parenchyma which is typical of all diseases involving perfusion defects of the liver. Although non-invasive imaging is sufficient for diagnosis, hepatic venography is still useful to determine the extent of the thrombosis, as well as to measure caval pressures to plan surgical treatment. Diagnostic accuracy of venography plus transjugular liver biopsy reaches 100% Prognosis and survival The natural history of BCS is not well known, as most publications report treated patients. Mortality rates have decreased over time [33,47]. In 120 patients, 5-year survival before 1985 was 50% compared with 75% thereafter. Mortality is highest within 2 years of diagnosis and independent of treatment in one study, with 77%, 65% and 57% of patients surviving 1, 6 and 10 years, respectively [47]. Clinicopathological factors, including treatment variables, derived from multivariable prognostic models are shown in Table 3 [35 38,47,48]. In the largest cohort of 237 patients the severity of encephalopathy, ascites, serum prothrombin time and bilirubin resulted in defining three groups with statistically different 5-year survival rates of 89%, 74% and 42% [35]. Histopathological features do not help to determine prognosis [35,38,47,49]; in only one study of surgical shunts (n = 24) was advanced fibrosis associated with increased mortality [48]. Chronic histological changes accompanying an acute presentation of BCS resulted in lower survival compared to acute or chronic BCS [36]. IVC obstruction has a good short-term prognosis, but there is a lack of long-term data [25]. In Japan, patients with obliterative cavopathy have a 25% mortality rate over 15 years. Most of these patients died from variceal bleeding, liver failure and hepatocellular carcinoma [34] Treatment Medical therapy and management of complications All patients should receive anticoagulation, unless strongly contraindicated, starting with intravenous heparin, then warfarin, to maintain INR at 2.5, if not higher. This treatment will control the disease in 10% of cases when the thrombosis is mild [50] and prevent progression, although there are no randomized trials [33,47]. Fulminant BCS is usually associated with abundant necrosis that ideally requires liver transplantation. Even in the setting of immediate shunting (surgical or TIPS), hepatic regeneration will rarely take place [51]. In patients with acute BCS, early thrombolytic therapy used within 72 h from diagnosis and infused directly into the thrombosed hepatic vein for 24 h, has had variable success [52].

5 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) Table 2 Prevalence of thrombophilic conditions and suggested screening in Budd Chiari Syndrome and EHPVO. (%) Diagnosis Notes BCS EHPVO Inherited conditions Antithrombin deficiency 5 1 Plasma level AT if no marked liver dysfunction Protein C deficiency Plasma level protein C if no marked liver dysfunction Protein S deficiency 5 7 <5 Plasma level protein S if no marked liver dysfunction Heterozygous factor V Leiden Heterozygous G20210A prothrombin Polymorprhism MTHFR Acquired conditions V617F JAK2 positive MPD V617F JAK2 negative MPD Activated protein C resistance if molecular test reveals Factor V Leiden mutation G1691A Molecular test for G20210A prothrombin gene mutation?? Elevated omocystein levels, C677T polymorphism Not clearly associated V617F JAK2 mutation in peripheral blood granulocytes 10? Bone marrow biopsy looking for clusters of dystrophic Megakaryocytes Increased factor VIII?? Plasma Factor VIII Risk factor associated with EHVPO Antiphosholipid syndrome Lupus anticoagulant, anti beta2-glycoprotein-1 antibodies, anticardiolipin antibodies Behcet s disease 3 5? Specific diagnostic criteria Usually young males and involvement of IVC PNH 2 5? Flow cytometry for CD55 and CD59 deficient blood cells Other conditions 5 10 Detailed medical history External factors Inflammatory bowel?? Medical history, colonoscopy diseases Hypereosinophilia rare? 5q minus Oral contraceptives in women 50? Medical history Screen for concomitant other thrombopgylic conditions Pregnancy Screening for all prothrombotic conditions Multiple factors including local factors 35 Search always for all possible causes Tumour CT scan No factors 5 Screening for familial prothrombotic conditions MPD: myeloproliferative disorders, PHN: parosysmal nocturnal hemoglobinuria. Compression by polycystic disease, abscesses, IFN, echinococchosis Table 3 Clinicopathological factors associated with prognosis of Budd Chiari syndrome. Henderson et al. [48] Tang et al. [38] Langlet et al. [36] Zeitoun et al. [47] Murad et al. [35] Number of patients 24 a Histological features Yes No Yes No No Higher serum transaminases ND Yes ND No No Higher Child-Pugh score No Yes Yes Yes Yes Ascites ND No No Yes Yes Hepatic encephalopathy ND No ND ND Yes Worse prothrombin time ND No Yes No Yes Higher serum bilirubin ND No Yes No Yes Older age at diagnosis ND Yes ND Yes No Higher serum creatinine Yes No No Yes No ND: not determined. a Patients who had shunt.

6 508 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) Adjunctive angioplasty or stent placement may not be of further therapeutic benefit [53] Angioplasty Short-segment obstruction or webs in hepatic veins or the IVC are treated successfully by balloon dilatation or intravascular stents. Membranous vena caval obstruction can be relieved initially in 90% of patients, but 20 30% will need additional angioplasty [54,55]. Eapen et al. reported 94% and 87% survival at 1 and 5 years in BCS patients with mild disease, according to the Murad classification, who were treated only by radiological intervention at a single centre [56]. Approximately half of all cases of re-thrombosis are due to suboptimal anticoagulation therapy. When there is diffuse thrombosis of hepatic veins, angioplasty alone is only successful in 56% of patients, even with additional thrombolytic therapy. On the other hand, stents have long-term patency rates of 80 90%, requiring further angioplasty in 50% [57]. Failure of thrombolysis or angioplasty and the presence of a diffuse hepatic vein thrombosis are indications for shunting Porto-systemic shunting The therapeutic principle of porto-systemic shunting is the conversion of the portal vein into an outflow tract (reversed portal flow), thus decompressing the sinusoids. Thrombosis or compression of the IVC mantains a high pressure in the infrahepatic IVC. Therefore a portacaval or mesocaval shunt will not provide decompression, whereas a shunt from the portal or mesenteric vein to the suprahepatic IVC or right atrium will be effective Surgical shunts Patients with a non-fulminant presentation of BCS and those without significant hepatic fibrosis who have a chronic presentation, can be considered for surgical shunting, providing the portal vein is patent. A side-to-side portal caval shunt (or meso-caval shunt) not only decompresses the liver, but also relieves ascites and eliminates the risk of variceal bleeding. A differential of 10 mmhg or more between the portal and intrahepatic IVC is considered essential [48]. A hypertrophied caudate lobe often makes the sideto-side portal caval shunt difficult to construct. If the IVC is patent but severely compressed, a self-expanding stent can be placed in the intrahepatic IVC, followed by a surgical infrahepatic shunt [58]. Surgical shunting should be performed in a liver transplantation centre where rescue therapy is possible. Moreover a TIPS procedure should be attempted before a surgical one, allowing a trial of shunting if this fails, liver transplantation is indicated Transjugular intrahepatic portosystemic shunts (TIPS) The use of TIPS has improved the management of BCS. TIPS avoids laparotomy, overcomes caudate lobe compression and occlusion of the IVC, with less mortality than surgical shunting, particularly in patients with poor liver function. Using TIPS does not preclude subsequent surgical shunting or liver transplantation [59 62]. With TIPS, the porto-caval pressure gradient should be normalized ( 6 mmhg). In three series, mortality rates ranged from 9% to 30% during a mean follow-up of 4 years. Amongst 65 patients, 7 died: 1 with fulminant liver failure (transplantation contraindicated), 4 with severe liver disease (acute on chronic presentation) and 3 with underlying haematological disorders. Long-term patency, despite routine anticoagulation therapy, only averaged 50%, with 36 72% of patients needing reintervention. TIPS can be placed even if there is portal vein thrombosis [22]. Polytetrafluoroethylene-covered stents results in patency rates of 67% at 1 year compared with 19% with uncovered stents, a very low rate compared with other series [59]. A recent cohort study on 124 patients with BCS who underwent TIPS in 6 centres in Europe showed that TIPS was able to improve survival according to Rotterdam score prediction with 5 years survival of 71% in high risk patients [63]. TIPS should be considered as first-line therapy, if variceal bleeding occurs, for acute and chronic BCS and also in patients with fulminant BCS if a liver donor is not available within 2 3 days. A recent report demonstrated that amongst 5 patients with fulminant liver failure, TIPS allowed resolution of the disease in 1, and acted as a bridge to liver transplantation within 1 month in 3 patients [64] Liver transplantation In the remaining 10% of patients, when percutaneous angioplasty or TIPS fail, liver transplantation should be considered. Emergency liver transplantation is indicated for fulminant BCS, and has been used as a salvage procedure for fulminant liver failure induced by surgical shunting [51,65,66]. There are 7 major transplant series, with more than 10 patients each, totalling 162 patients (Table 4), with survival rates between 50% and 95% with a mean follow up of 4.5 years [51,67 70]. Twenty patients (12%) had acute portal vein or hepatic arterial thrombosis, or late thrombosis, which was fatal in 8 and resulted in retransplantation in 8. Despite anticoagulation recurrent BCS occurred in 2 of 7 transplanted patients [71]. Recently a retrospective analysis of series from U.S.A. [72] and Europe [73] has shown a 5 years survival rate of 80%. However, TIPS was placed in only 4% of patients before transplant in the European series and anticoagulation was used in less than 60%. Recurrence of venous thrombosis or BCS occurred in about 10% of patients confirming the need for anticoagulation. Although almost all genetic thrombophilic disorders are cured by transplantation [65,74], thrombosis still occurs and routine anticoagulation therapy is necessary. Careful monitoring is necessary as complications of anticoagulation were seen in 40% [71] and 17/197 (11%) transplanted patients had bleeding complications due to anticoagulation after transplant leading to 2 death in the European series. In patients with myeloproliferative disorders who underwent liver transplantation, the use of hydroxyurea and aspirin was safe and effective [75]. So far malignant transformation is anecdotal [69,73]. A suggested algorithm of treatment for BCS is illustrated in Fig Veno occlusive disease/sinusoidal obstruction syndrome 3.1. Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a clinical syndrome characterized by hepatomegaly, ascites, weight gain and jaundice [76,77]. VOD is described with alkaloids, alcohol, oral contraceptives, toxic oil, drugs such as terbinafine, or radiation injury. Hemopoietic stem cell transplantation (SCT) has become the most important and frequent cause of VOD. The incidence of VOD after SCT ranges from 0% to 70%, dependent on diagnostic criteria, the sample size and risk factors which are heterogenous amongst different cohorts [78]. Currently, the incidence and severity of VOD after SCT is decreasing due to earlier timing of SCT in patients with leukaemia, the use of nonmyeloablative regimens and the decrease of HCV infection amongst transplant candidates [79]. VOD is also reported after other solid organ transplantation, particularly kidney transplantation with incidence of 2 5% (5/200 kidney transplants), mainly related to azathioprine toxicity. In liver transplant recipients the largest series reported an incidence of 1.9%

7 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) Table 4 Liver transplantation for Budd Chiari syndrome. Halff et al. Jamieson et al. Ringe et al. Srinivastan et al. Ulrich et al. Metha et al. Segev et al. Patients Mean interval from diagnosis to OLT (months) 13 ND ND 8 ND 55.8 NA Follow-up (years) Survival 88% 50% 69% 95% 87% 68% 80% Recurrence of disease/thrombosis 17% 13% 9% 21% 15% 11% NA OLT: orthotopic liver transplantation; ND: not determined. (19/1023 liver transplants) clinical VOD, related to the number and severity of rejection episodes and azathioprine use Pathophysiology and histology After SCT, high-dose chemotherapy produces endothelial injury of both sinusoids and small hepatic venules in patients with particular susceptibility. The sinusoidal damage leads to activation of the coagulation cascade, and clot formation. Fibrin-related plugs, intracellular fluid entrapment and cellular debris progressively occlude sinusoids, causing intrahepatic post sinusoidal portal hypertension, responsible for the clinical signs of fluid retention (weight increase), hepatomegaly, ascites and jaundice. Usually fibrosis occurs several weeks after the onset of the disease [80]. All these injuries cause depletion of glutathione from hepatocytes, resulting in increased sensitivity to zone 3 damage due to other compounds which can further deplete glutathione, such as cyclophosphamide, busulfan and BCNU. Vasoconstriction related to nitric oxide (NO) depletion occurs, further incrementing the damage [81]. Early histological abnormalities include sinusoidal congestion associated with centrilobular necrosis; later fibrous obliterative lesions in the hepatic venules occur with histologic damage located to zone 3 of the acinus Clinical presentation and diagnosis The classic presentation of VOD is characterized by the triad of weight gain caused by fluid retention, tender hepatomegaly and hyperbilirubinaemia of unknown cause [81,82]. Usually this occurs within days after SCT when regimens containing cyclophosphamide have been used. After liver transplantation VOD occurs over a wide interval, with a mean of 9 weeks after transplant. Diagnosis is usually based on signs and symptoms, having ruled out other conditions which can mimic the disease particularly after SCT, such as viral infections and graft versus host disease, cholestasis secondary to sepsis, heart failure and tumoral infiltration of the liver [83]. Nowadays, clinical parameters have been formalized in the Baltimore and Seattle criteria. Ultrasound with doppler examination is the first line imaging investigation. Findings include the presence of ascites, hepatomegaly, attenuated hepatic veins and/or biliary dilatation. Significant elevation of the hepatic artery resistive index in duplex sonography may be a sensitive index of liver damage related to VOD. In infants, a segmental portal flow reversal has also been shown to be strongly associated with early VOD [84]. Fig. 1. Algorithm for diagnosis and treatment of Budd Chiari syndrome. BCS: Budd Chiari syndrome; IVC: inferior vena cava; PV: portal vein; TJ: transjugular; HV: hepatic vein; PVT: portal vein thrombosis; FHF: fulminant hepatic failure; TIPS: transjugular intrahepatic portosystemic shunt.

8 510 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) Table 5 Diagnostic criteria of veno-occlusive disease after stem cell transplantation (SCT). Seattle criteria At least two of the three following criteria: within the first month after SCT: 1. Jaundice 2. Hepatomegaly and right upper quadrant pain 3. Ascites and/or unexplained weight gain Baltimore criteria Elevated total serum bilirubin ( 2 mg/dl) before day 21 after SCT and two of the following three criteria: 1. Tender hepatomegaly 2. Weight gain >5% from baseline 3. Ascites Modified Seattle criteria Occurrence of two of the following events within 20 days of SCT: 1. Hyperbilirubinaemia ( 2 mg/dl) 2. Hepatomegaly or right upper quadrant pain of liver origin 3. Unexplained weight gain (>2% of baseline bodyweight) because of fluid accumulation 3.4. Haemodynamics and hepatic vein catetherization Transjugular access is a safe route to perform measurement of hepatic venous pressure gradient (HVPG) and liver biopsy [85]. The absence of a significant gradient (<6 mmhg) along the hepatic veins and in the IVC can exclude anatomical causes of outflow obstruction. In one study a HVPG greater than 10 mmhg was significantly correlated with VOD (91% specificity and 86% positive predictive value) [86]. HVPG can be also helpful to determine prognosis, as patients who will survive with VOD have less severe portal hypertension. HVPG greater than 20 mmhg is correlated with poor prognosis [76] Prognosis and outcome Bearman et al. developed a model to estimate survival in patients with VOD based on a large cohort of SCT patients. Greater weight gain, serum bilirubin, ascites and peripheral oedema were associated with worse survival. Severe VOD was associated with 98% mortality at day 100 after SCT (Table 5). Moreover HVPG greater than 20 mmhg was confirmed as an independent prognostic marker of mortality [76]. Outcome of VOD after liver transplantation is reported by Sebagh et al. with 63% mortality (12 of 19 patients) in the largest series published. Mortality after liver transplantation is related mainly to liver failure and development of renal insufficiency due to portal hypertensive complications [87] Therapy Prevention Treatment of VOD is primary supportive and spontaneous recovery is reported in 70 85% of mild forms after stem cell transplantation. However severe forms do not resolve and given the paucity of effective therapies, prevention is a priority. The use of nonmyeloablative regimens in patients with risk factors for VOD is now possible and is the most important preventive measure. Prophylactic administration of ursodeoxycholic acid, as an antioxidant and antiapoptotic agent, has been evaluated in 4 randomized trials [88 91] and in the most recent two (one in combination with heparin) no benefit of UDCA administration per se or when added to heparin was seen. Prostaglandin E1 is a vasodilator with protective properties for the endothelium and antithrombotic activity. One nonrandomized trial in which PGE1 was given in combination with heparin or with heparin and tpa showed a lower incidence of VOD in the PGE1 group (12.2% versus 25.5%), however, the most recent prospective study enrolling 24 patients using PGE1 alone failed to show any advantage and was associated with severe toxicity in all [81] Treatment Treatment of the classical syndrome also includes supportive measure aiming to treat complications. Based on the histological presence of microthrombosis and fibrin deposition in the hepatic venules of patients with VOD, the principal specific therapy has been to promote fibrinolysis with or without anticoagulation [91]. To date, about 130 patients have been treated with tpa, and the response rate is about 30% in the largest series with the addition of concomitant heparin. However, no response was seen amongst patients with multi-organ, renal or respiratory failure. Thus, administration of fibrinolytics and anticoagulants should be avoided in these patients, but conversely they should be given early in the course of VOD. Administration of antithrombin and protein C or PGE1 has not been shown to be effective [92]. However, there is some evidence for the use of defibrotide, a deoxyribonucleic acid derivative which shares fibrinolytic and antithrombotic properties. In the largest series published, treatment with mg/kg infusion of defibrotide every 6 h achieved a response rate of 36% and overall survival rate of 35% at 100 days after SCT without adverse events [93]. The high mortality rate of VOD after liver transplantation underlines the need for specific therapy. In the two patients treated with defibrotide for VOD after LT, only one survived. No effective medical therapy has been reported. Decompression of the engorged sinusoids by a transjugular intrahepatic portosystemic shunt can relieve portal hypertension and prevent renal failure in patients with VOD. To date 27 VOD patients treated with TIPS have survived, 20% of the total. If multiorgan failure (MOF) is already present, treatment is likely too late. Thus, although TIPS is not recommended for patients with severe VOD, this may apply only to SCT patients in whom MOF conditions the prognosis. Liver transplantation has been reported as a rescue therapy in patients with VOD after SCT not responding to medical therapy. To date 18 patients have been reported to be transplantated due to VOD/SOS with 13 deaths (72%), primarily due to infectious complications. When VOD develops after liver transplantation itself, retransplantation can be performed as a rescue therapy as the liver is the only damaged organ. A flow-chart for the suggested diagnosis and management of VOD is illustrated in Fig Liver involvement in hereditary hemorrhagic telangiectasia (Rendu Osler Weber syndrome) 4.1. Introduction Hereditary hemorrhagic telangiectasia (HHT) or Rendu Osler Weber disease is a genetic disease inherited in an autosomal dominant pattern with variable penetrance [94] characterized by diffuse telangiectasias involving the skin, mucous membranes, lung, brain, the gastrointestinal tract and the liver, with a prevalence of 1 2 cases per 10,000 [88,95]. The prevalence of hepatic involvement in HHT has been estimated to be between 32% and 72% by ultrasonography or CT scan [96]. Vascular liver involvement is very variable, leading to small telangectasiae or vascular shunts between hepatic artery and hepatic veins (artero-venous), hepatic artery and portal vein (artero-portal) or portal vein and hepatic veins (porto-venous). The three types of shunting likely occur concomitantly, but usually one of them

9 M. Senzolo et al. / Digestive and Liver Disease 43 (2011) Fig. 2. Algorithm for diagnosis and treatment of veno occlusive disease. VOD: veno occlusive disease; SCT: Stem cell transplantation; LT/OLT: liver transplantation; US: ultrasound; MRI: magnetic resonance; HVPG: hepatic venous pressure gradient; HV: hepatic veins; IVC: inferior vena cava; TIPS: transjugular intrahepatic portosystemic shunt; KTx: kidney transplantation. predominates functionally though the balance may change over time Diagnosis The clinical criteria for HHT diagnosis, known as the Curaçao criteria, have been established by a panel of experts [89] (Table 6). The diagnosis of HHT is considered definite if 3 or more criteria are present, possible or suspected if 2 criteria are present, and unlikely if 0 or 1 criterion is present. Genetic testing is available by analysis of a chromosome 9 mutation of the gene encoding for endoglin, and a chromosome 12 mutation of a gene encoding for activin receptor-like kinase type 1 [90]. These two genetic forms are defined as HHT1 and HHT2 respectively, and represent about 90% of total HHT cases [88,91]. Phenotypic expression of the disease is complete usually within 40 years of age. Cerebral vascular malformations are present in 9 20% of patients with HHT1 and 0 4% of patients with HHT2, whereas pulmonary vascular malformations are present in 54 75% and 12 44% in HHT1 and HHT2 respectively [90]. Table 6 Diagnostic criteria for diagnosis of hereditary hemorrhagic telangiectasia (HHT) according to Curaçao criteria [91]. Criteria Epistaxis Telangiectasias Visceral lesions Family history Description GI: gastrointestinal; AVM: artero-venous malformations. Spontaneous and recurrent Multiple, at characteristic sites: lips, oral cavity,fingers, nose GI Telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs A first degree relative with HHT according to these criteria 4.3. Clinical manifestations Only 8% of patients with liver involvement in HHT are reported as symptomatic [91,92]. High output heart failure is the most common manifestation in adult to middle age patients [91]. Portal hypertension develops due to the presence of intrahepatic shunts between hepatic artery and portal vein or the presence of large regenerative nodules; portal pressure measurement by the hepatic venous pressure gradient (HVPG) demonstrates a sinusoidal type of portal hypertension [92]. Ischemic lesions of the biliary tree cause the development of strictures and/or dilatation, leading rarely to ductal necrosis or cholangitis [91,93,96,97]. The most common biochemical abnormalities are elevation of alkaline phosphatase and GGT, whilst liver synthetic function is usually normal. When liver failure is present it is usually associated with biliary/hepatic necrosis. Notably, platelet count is normal in all patients, even those with portal hypertension [92,94]. Hepatic encephalopathy is a rare presentation, as well as recurrent abdominal angina due to mesenteric arterial steal by vascular liver malformations Diagnosis of liver involvement in Hereditary hemorrhagic telangiectasia Liver involvement by HHT is investigated by imaging studies during screening of HHT families, when establishing the diagnosis of HHT (visceral involvement is one of the diagnostic criteria for HHT, therefore finding liver vascular malformations in a patient with one or two Curaçao criteria can further clarify the diagnosis) or when the suspicion is raised by clinical symptoms/signs [96]. The diagnosis of liver involvement in HHT requires laboratory assessment and imaging: Doppler ultrasound has been proposed as a screening technique given its accuracy for the detection and grading of liver vascular malformations, its non-invasiveness, availability, repeatability and low cost [98]. Further testing (either