Vascular disorders of the liver # †
Authors: Laurie D. DeLeve, Dominique-Charles Valla, Guadalupe Garcia-Tsao
Journal: Hepatology (2008)

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines.3, 4) AASLD, American Association for the Study of Liver Diseases; BCS, Budd-Chiari syndrome; CT, computed tomography; DVT, deep vein thrombosis; HHT, hereditary hemorrhagic telangiectasia; HV, hepatic vein; IVC, inferior vena cava; LVM, liver vascular malformation; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; NRH, nodular regenerative hyperplasia; PVT, portal vein thrombosis; SOS, sinusoidal obstruction syndrome; TIPS, transjugular intrahepatic portosystemic stent shunt. The major vascular disorders of the liver are listed in Table 2. Most of the vascular disorders of the liver are rare, with the exception of portal vein thrombosis (PVT) in patients with cirrhosis, and therefore the best evidence about diagnosis and management has been acquired through prospective cohort studies rather than randomized clinical trials. Their importance lies in the very significant morbidity and mortality that can occur without timely diagnosis or disease-specific management or even with an inappropriate workup. The purpose of these guidelines is to provide clinicians with approaches to diagnose and manage the disorders for which there are sufficient data to make recommendations. Given the rarity of some of the vascular disorders, not all are suitable for practice guidelines, and these will not be discussed. These guidelines will review PVT, sinusoidal obstruction syndrome, Budd-Chiari syndrome (BCS), and congenital vascular malformations. Obstruction of the portal vein or its branches can be related to invasion or constriction by a malignant tumor, or to thrombosis. In developed countries, PVT might be more common than previously considered, as it was found at routine necropsy in about 1% of Swedish subjects in the 1970s.5 In developing countries, PVT has accounted for up to 30% and 75% of cases of portal hypertension in adults and children, respectively.6 From a clinical point of view, PVT consists of two different entities, acute PVT and chronic PVT, which represent successive stages of the same disease and share similar causes, but differ as to their management.7 Therefore, after considering their common causal factors, acute and chronic PVT will be discussed successively. Likewise, PVT occurring in children, in patients with cirrhosis, and in liver transplant recipients will be considered separately, because their features and management differ from those in other groups of patients. PVT is caused by a combination of local and general risk factors. A local risk factor can be identified in about 30% of patients, and a general risk factor in 70%.7-11 A list of these local risk factors is provided in Table 3. Malignant tumors within the portal venous territory (in the absence of portal venous invasion or constriction), and cirrhosis are the leading local risk factors for PVT.5, 9 In the rest of the patients, the most common local factor for PVT is inflammatory foci in the abdomen.7, 12, 13 A local factor for PVT is more frequently recognized at the acute stage of PVT than later on at the chronic stage.7 General risk factors are similar in nature and in prevalence in patients with acute PVT and chronic PVT.7 As shown in Table 4, an inherited or acquired prothrombotic condition has been found in many patients with PVT, whether a local risk factor had been identified.8, 9, 11, 14-19 Therefore, identification of a local risk factor does not exclude the possibility that a general risk factor is present. Malignancy is a well-established, although not fully understood, risk factor for deep vein thrombosis (DVT).20 This malignancy-associated prothrombotic state may play a role in PVT developing in patients with malignant abdominal tumors in the absence of compression or invasion. Likewise, systemic inflammatory response is a major general risk factor for thrombosis.21 In the context of acute PVT, however, it is difficult to determine whether inflammation is a cause or consequence of PVT. In young adults without cancer or cirrhosis, PVT is frequently the presenting manifestation of a myeloproliferative disease.11, 22 Overall, 30%–40% of patients with PVT are affected with chronic, Philadelphia-negative myeloproliferative diseases, usually polycythemia vera, essential thrombocythemia, or unclassified myeloproliferative diseases. However, due to portal hypertension and/or iron deficiency, the peripheral blood changes suggestive for a myeloproliferative disease are lacking in most affected patients.23 Furthermore, splenic enlargement is not specific for a diagnosis of myeloproliferative disease in a context of portal hypertension. Clusters of dystrophic megakaryocytes at bone marrow biopsy22 and endogenous erythroid colony formation in culture of bone marrow or circulating progenitors23 have been used in the past to make a diagnosis of occult or masked myeloproliferative disease. Recently, 1849G→1849T point mutation (V617F) of the tyrosine kinase Janus kinase 2 (JAK2) gene in myeloid cells has proved a highly specific and easily detectable marker for myeloproliferative disease. Among 388 patients with noncancerous, noncirrhotic PVT in four studies, this mutation was found in 21%–37% of patients with PVT.24-27 However, in 5%–10% of patients with PVT, this specific mutation was undetectable whereas bone marrow biopsy and assessment of endogenous erythroid colonies provided evidence for a myeloproliferative disease. Identification of inherited deficiency of natural coagulation inhibitors can be difficult.9, 11 In patients with acute PVT, the systemic inflammatory response may alter baseline levels of these inhibitors. In patients with chronic PVT, there can be a nonspecific decrease in the synthesis of coagulation factors and inhibitors even when liver dysfunction is not obvious.28 The concurrence of several prothrombotic disorders in a patient with PVT is more frequent than expected in the general population.9, 11 Thus, the identification of a risk factor for thrombosis does not exclude other factors. The role of oral contraceptive use and pregnancy as causal factors for PVT is less clear than for thrombosis at other sites.9, 11 In patients with cirrhosis, the risk of developing PVT has been related to the severity of liver disease, and to the presence of inherited prothrombotic disorders.29 In patients with impaired synthetic function and low plasma levels of natural coagulation inhibitors, there is currently no simple means for ascribing such low levels to a preexisting deficiency. In patients with cirrhosis and portal venous obstruction, invasion by hepatocellular carcinoma should be ruled out before making a diagnosis of bland thrombosis.30, 31 Recommendations for investigating causes of PVT: 1. Check first for cirrhosis, cancer of the abdominal organs, and an inflammatory focus in the abdomen, based on initial computed tomography (CT) scan and sonography findings, followed by additional procedures, as appropriate (Class I, Level B). 2. Check for multiple, concurrent risk factors for thrombosis, in all patients without advanced cirrhosis or cancer, as indicated in Table5 (Class I, Level B). 3. Do not rule out a diagnosis of myeloproliferative disease solely on the basis of normal or low peripheral blood cell counts (Class I, Level B). 4. When coagulation factor levels are decreased, consider low levels of protein C, protein S, or antithrombin as a possible consequence of liver dysfunction; consider inherited deficiency when screening of a first-degree relative is positive (Class I, Level C). Acute PVT is characterized by the sudden formation of a thrombus within the portal vein. The thrombus can involve a variable portion of the mesenteric veins and/or the splenic vein. Occlusion can be complete or it can be partial, leaving a peripheral circulating channel. Acute PVT has been rarely reported in children. Therefore, this section will focus on data collected in adults. PVT occurring in patients with cirrhosis will be discussed separately. Acute septic PVT is frequently referred to as acute pylephlebitis. This entity is characterized by the presence of infected thrombus/thrombi.32 Acute PVT usually presents with abdominal or lumbar pain of sudden onset or progressing over a few days.7, 33, 34 The abdomen might be moderately distended by ileus, but without any other features of intestinal obstruction. There is no guarding, except when an inflammatory focus is the cause for PVT or when PVT is complicated with intestinal infarction. The contrast between severity of pain and the absence of peritoneal signs has long been regarded as suggestive of mesenteric venous thrombosis in the differential diagnosis of peritonitis.33, 35 Partial thrombosis might be associated with fewer symptoms. Rapid and complete obstruction of the portal vein or mesenteric veins, without involvement of mesenteric venous arches, induces intestinal congestion, manifested by severe continuous colicky abdominal pain and occasionally nonbloody diarrhea.33 A marked systemic inflammatory response is common in patients with acute PVT in the absence of sepsis. Persistent, nonspiking fever and abdominal pain are usual. Plasma levels of acute phase reactants are frequently and sometimes markedly elevated. Liver function is preserved in patients with acute PVT, probably because increased hepatic arterial blood flow compensates for the decreased portal inflow; and because a collateral circulation develops rapidly from pre-existing veins in the porta hepatis.36 However, a transient, moderate increase in serum aminotransferases can be observed in some patients. Provided there is no extension of the thrombus to mesenteric venous arches, all manifestations of acute PVT are completely reversible, either by recanalization or by development of a cavernoma.7 When extensive thrombosis involves distal mesenteric veins, intestinal ischemia and eventually infarction can occur. The occurrence of infarction is probably related to complete obstruction of venous outflow (the mesenteric arches can no longer serve as collateral pathways), and to reflex arterial constriction and occlusion.33 Clinical features that suggest a patient has transmural intestinal ischemia include persistence of severe pain beyond 5–7 days, bloody diarrhea, and ascites.35 Acidosis and renal or respiratory dysfunction are also suggestive of intestinal infarction.37 In the absence of treatment, intestinal perforation, peritonitis, shock, and death from multiorgan failure occur.37 Clinical features of pylephlebitis include a high, spiking fever with chills, a painful liver, and sometimes shock. Blood cultures usually grow Bacteroides species, with or without other enteric species. Multiple, small liver abscesses are common in this setting. Acute septic PVT is always associated with an abdominal focus of infection.7, 12, 32 This primary focus can be easily overlooked clinically and, therefore, detected only by careful review of the CT scan or magnetic resonance imaging (MRI).38 Sepsis-related cholestasis can be present. In most patients, the diagnosis of acute PVT can be rapidly established using noninvasive imaging.39-43 Sonography can show hyperechoic material in the vessel lumen with distension of the portal vein and its tributaries. Doppler imaging shows the absence of flow in part or all of the lumen.44 A CT scan without contrast can show hyperattenuating material in the portal vein. After injection of contrast agent, lack of luminal enhancement, increased hepatic enhancement in the arterial phase, and decreased hepatic enhancement in the portal phase are shown.45, 46 For the assessment of thrombus extension within the portal venous system, CT or MR angiography are more sensitive techniques than Doppler sonography, because the mesenteric veins are more difficult to visualize with ultrasound. Thinning of the intestinal wall or lack of mucosal enhancement of a thickened intestinal wall after intravenous contrast injection are further pieces of evidence for intestinal infarction.47 Enlargement of pre-existing veins in the porta hepatis are seen as early as a few days after the onset of acute PVT. This is particularly conspicuous in the gallbladder wall, which is thickened and enhances after contrast injection, and should not be confused with acute cholecystitis.48 Recommendations for diagnosis of acute PVT: 5. Consider a diagnosis of acute PVT in any patient with abdominal pain of more than 24 hours duration, whether or not there is also fever or ileus (Class I, Level B). 6. If acute PVT is suspected, CT scan, before and after injection of vascular contrast agent, should be obtained for early confirmation of diagnosis. If CT scan is not rapidly available, obtain Doppler-sonography (Class I, Level B). 7. In patients with acute PVT and high fever and chills, septic pylephlebitis should be considered, whether or not an abdominal source of infection has been identified, and blood cultures should be routinely obtained (Class I, Level B). 8. In acute PVT, the possibility of intestinal infarction should be considered from presentation until resolution of pain. The presence of ascites, thinning of the intestinal wall, lack of mucosal enhancement of the thickened intestinal wall, or the development of multiorgan failure indicate that intestinal infarction is likely and surgical exploration should be considered (Class I, Level B). The goal of treatment of acute PVT is to recanalize the obstructed veins, which will prevent intestinal infarction and portal hypertension. Correction of the causal factors, which should be achieved as soon as possible, is beyond the scope of these guidelines. In the presence of fever or leukocytosis, antibiotics have been used, whether bacterial infection was eventually documented. There are reports of recanalization of pylephlebitis with antibiotic therapy alone.12, 49 Anticoagulation therapy is of proven benefit in patients with acute DVT.50 Extrapolation to patients with acute PVT is logical but still not firmly validated. There have been no controlled studies of anticoagulation therapy in patients with acute PVT. Four retrospective surveys—all reported before 2000—included consecutive patients. Their combined data show that when initiated immediately, 6 months of anticoagulation therapy was associated with complete recanalization in 50% of patients, partial recanalization in about 40% of patients, and no recanalization in 10% of patients.7 Spontaneous recanalization appears to occur infrequently in unselected patients not given anticoagulation therapy.7 High recanalization rates have also been reported in patients given anticoagulation therapy for postsplenectomy PVT,51 or for acute thrombosis involving the superior mesenteric vein.7, 34, 49, 52 Major complications of anticoagulation therapy were reported in less than 5% of treated patients.7 The optimal duration of anticoagulation therapy for acute PVT has not been determined. Complete recanalization can be delayed until the sixth month of anticoagulation therapy.7, 34, 41 A panel of international experts has recommended that in patients with acute PVT, anticoagulation be given for at least 3 months, and permanent anticoagulation therapy be considered for patients with permanent prothrombotic conditions.53 In patients with DVT, a lack of complete recanalization indicates a high risk of recurrence after cessation of anticoagulation therapy.54 It remains to be assessed whether this is also true for patients with acute PVT. The reported experience with other treatment modalities (surgical thrombectomy, systemic or in situ thrombolysis, or transjugular intrahepatic portosystemic stent shunt [TIPS]) in the treatment of acute PVT is extremely limited.55, 56 One study analyzed the outcome in 20 patients treated with thrombolysis administered into the superior mesenteric artery or, through transhepatic puncture, in the portal vein.55 There was complete recanalization in three patients (15%), partial recanalization in 12 (60%), and no recanalization in five patients (25%). Twelve patients (60%) developed major procedure-related complications, and one patient died as a result.55 In another retrospective survey, patients treated with thrombolytic agents had significantly increased mortality.57 There has been no formal comparison of the risk/benefit ratio of these procedures with that of anticoagulation alone. However, compared to anticoagulation alone, invasive procedures appear not to be more effective while being more dangerous. When clinical and radiological features indicate that a patient has intestinal infarction, emergency laparotomy for resection of the overtly necrotic parts of the gut should be performed.35, 58 The risk of postoperative malabsorption is related to the extent of intestinal resection. Moreover, the extent of irreversible lesions can be overestimated at gross inspection. Therefore, various procedures have been proposed to limit the extent of intestinal resection while coping with the risk of necrosis after operation.58 This aspect is beyond the scope of the present guidelines. Surgical thrombectomy can be performed at the time of the resection/laparotomy. Anticoagulation therapy appears to improve the survival of patients who undergo surgery.58, 59 When acute PVT is recognized and treated before intestinal infarction occurs, the outcome is good.7, 34, 49, 52, 57, 60 Abdominal pain and systemic inflammatory syndrome start subsiding within a few hours to a few days after initiation of anticoagulation. Intestinal infarction is prevented when the superior mesenteric vein remains patent or has recanalized. Portal hypertension is prevented when the portal vein trunk and at least one of its two branches remains patent or has recanalized. Among 31 patients given prolonged anticoagulation therapy for acute PVT, bleeding occurred in two patients: from ruptured esophageal varices in one patient whose portal vein had not recanalized, and from an ovarian cyst in the other.7 A few patients may develop delayed intestinal obstruction as a result of intestinal ischemia and stricturing.60, 61 Overall mortality rate appears to have decreased from 30% to about 10% during the last decade, and currently most deaths are related to postoperative complications or underlying disease.37 Recommendations for the treatment of acute PVT (see also Table6): 9. Give anticoagulation therapy for at least 3 months to all patients with acute PVT. Start with low molecular weight heparin in order to achieve rapid anticoagulation. Shift to oral anticoagulation as soon as the patient's condition has stabilized, when no invasive procedure is planned (Class I, Level B). 10. Continue on long- term anticoagulation therapy in patients with acute PVT and permanent thrombotic risk factors that are not correctable otherwise (Class I, Level B). 11. In the absence of contraindication, also consider long term anticoagulation for patients with acute PVT and thrombus extension distal into the mesenteric veins (Class IIa, Level C). 12. Initiate antibiotics promptly in patients with acute PVT and any evidence of infection (Class I, Level C). In patients with chronic PVT, also known as portal cavernoma, the obstructed portal vein is replaced by a network of hepatopetal collateral veins connecting the patent portion of the vein upstream from the thrombus to the patent portion downstream. The number, size, and location of collaterals is extremely variable from patient to patient. With occlusion of the trunk of the portal vein, antral, duodenal and biliary veins are markedly enlarged. This enlargement can produce compression and deformation of large bile ducts, so-called portal cholangiopathy or portal biliopathy.62, 63 With occlusion at the origin of the portal vein, pancreatic veins are enlarged. Complete occlusion of the portal vein trunk, or of its two main branches is virtually always associated with portal hypertension and the development of portosystemic collaterals. In developed countries, there is a clear time trend for earlier recognition of PVT at the acute stage.7 Moreover, the classical presentation of cavernoma with ruptured esophageal or gastric varices is now rare. At present, diagnosis is commonly made after a fortuitous finding of hypersplenism or portal hypertension. Biliary symptoms related to portal cholangiopathy (jaundice, biliary pain, cholangitis, cholecystitis, or pancreatitis) rarely reveal a cavernoma.62, 63 Gastrointestinal bleeding is regarded as better tolerated than in other forms of portal hypertension probably because patients are usually younger and have no liver dysfunction. The occurrence of ascites or encephalopathy in patients with chronic PVT is uncommon, and is usually encountered only transiently following gastrointestinal bleeding or when there is unrelated renal failure or marked sepsis in older patients.64 Features of subclinical encephalopathy, however, can be demonstrated in half of the patients.65 Liver tests are typically normal in patients with portal cavernoma in the absence of underlying liver disease. Coagulation factor levels can be moderately altered. Portal cholangiopathy should be considered when there are cholestatic features. Hepatopulmonary syndrome is present in about 10% of patients.66 A diagnosis of cavernoma is readily made by abdominal imaging with ultrasound, CT or MRI which shows serpiginous structures while the main portal vein and/or its main branches are not visible.40, 46, 67 Hepatic arteries are usually enlarged. In the absence of cirrhosis, there might be an enlarged caudate lobe, together with an atrophic left lateral segment or right lobe of the liver. Typically, the umbilical vein is not dilated as it connects to the left portal vein branch downstream of the obstruction. In some patients a large, prominent collateral vein at the porta hepatis can be mistaken for a normal portal vein. A cavernoma that has developed in the pancreatic area might be confused with an enlarged pancreas. Portal cholangiopathy, which mimics the bead-like appearance of primary sclerosing cholangitis, is much more commonly seen on biliary tract imaging than clinical or laboratory features of biliary disease would suggest.62 A tumor-like cavernoma can be confused with carcinoma of the main bile duct. This particular and rare form of chronic PVT is characterized by tiny collateral channels forming a mass that encases the main bile duct, and enhances at the portal phase of contrast injection.62 Endosonography and MR angiography and cholangiography appear to be of great help in clarifying these differential diagnoses.68, 69 Recommendations for diagnosis of chronic PVT: 13. Consider a diagnosis of chronic PVT in any patient with newly diagnosed portal hypertension (Class I, Level B). 14. Obtain Doppler-sonography, then either CT scan or MRI, before and after a vascular contrast agent, to make a diagnosis of chronic PVT. 15. Base the diagnosis on the absence of a visible normal portal vein and its replacement with serpiginous veins (Class I, Level B). Therapy for chronic PVT can be separated into three areas: prevention and treatment of gastrointestinal bleeding; prevention of recurrent thrombosis; and treatment of portal cholangiopathy. There have been no controlled studies of beta-adrenergic blockers or endoscopic therapy in patients with chronic PVT. Nevertheless, screening for gastro-esophageal varices, and beta-adrenergic blockers or endoscopic therapy for patients with large varices might be carried out for patients with portal cavernoma, as is done for patients with cirrhosis.53, 70 Indeed, retrospective multivariate analyses found that their application reduced the risk of first bleed or recurrent bleeding,64 or improved survival.71 Endoscopic sclerotherapy has achieved eradication of varices and a reduction in the number of bleeding episodes in uncontrolled surveys.72, 73 Data on endoscopic ligation are lacking in adult patients with chronic PVT. For primary prophylaxis of variceal bleeding there are insufficient data on whether beta-blockers or endoscopic therapy should be preferred. Contrasting findings have been reported regarding the feasibility and the outcome of surgical portosystemic shunting, which suggests differences in patient selection or referral.74, 75 Data on splenectomy and devascularization are limited. There are anecdotal reports of successful TIPS insertion in patients with a portal cavernoma in the absence of cirrhosis.76 However, this procedure is not technically feasible in most patients. Randomized controlled trials of anticoagulation therapy for the prevention of recurrent thrombosis are lacking. The frequent association with permanent prothombotic disorders on the one hand and the risk of intestinal infarction on the other support the use of anticoagulation. However, an increased risk of bleeding from portal hypertension raises concerns. In a retrospective multivariate analysis of a large cohort including patients with chronic or acute PVT, it was found that anticoagulation therapy significantly decreased the risk of recurrent thrombosis without increasing the risk of gastrointestinal bleeding.64 The severity of bleeding was similar with or without anticoagulation therapy and there were no bleeding-related deaths in patients receiving anticoagulation. Owing to the scarcity of data, however, an expert panel recommended that anticoagulation therapy be considered only in patients with a documented permanent prothrombotic condition.53 Recently, a retrospective study showed that warfarin administration independently improved survival of patients with chronic portomesenteric venous thrombosis, most of whom had a risk factor for thrombosis.71 Another uncontrolled retrospective survey found a decreased incidence of gastrointestinal bleeding following initiation of anticoagulation therapy.77 In patients with jaundice or recurrent biliary symptoms due to cholangiopathy, insertion of a biliary endoprosthesis after endoscopic extraction of secondary stones resulted in half the patients having no recurrence when the prosthesis was removed after some time.68 The procedure needs to be repeated when symptoms recur. Portosystemic shunting primarily performed to address the biliary complications, has been used where feasible in a limited number of patients; bilioenteric anastomosis was necessary in two of the eight shunted patients.78 Biliary surgery without portal decompression is extremely hazardous. Recurrent bleeding from portal hypertension is the most common complication, followed by recurrent thrombosis at splanchnic or extrasplanchnic sites.64, 71 However, the current outcome for treated patients with chronic PVT is good. In patients followed up for 5 years, less than 5% died from the classical complications of PVT (intestinal infarction or gastrointestinal bleeding).64 Mortality is related mainly to age, cause of PVT, or unrelated diseases. The long-term prognosis in patients with portomesenteric venous obstruction might be poorer than in those with obstruction limited to the portal vein.71 Prolongation of life expectancy due to better control of bleeding and thrombotic risks probably explains why long term complications are predominantly related to cholangiopathy62, 63 and to transformation of underlying myeloproliferative disease into myelofibrosis or acute leukemia.22 Recommendations for treatment of chronic PVT (See also Table6): 16. Screen all patients with chronic PVT for gastroesophageal varices, and apply treatment for active variceal hemorrhage and for primary and secondary prophylaxis according to guidelines for patients with cirrhosis (Class I, Level B). 17. Consider long-term anticoagulation therapy in patients with chronic PVT, without cirrhosis, and with a permanent risk factor for venous thrombosis that cannot be corrected otherwise, provided there is no major contraindication. In patients with gastroesophageal varices, do not initiate anticoagulation until after adequate prophylaxis for variceal bleeding has been instituted (Class IIa, Level C). The theory that extrahepatic portal vein obstruction in this age group always results from thrombosis, as opposed to a congenital origin, has not been fully documented and is still debated.79, 80 The prevalence of underlying prothrombotic diseases was high in most but not all studies.81-86 Primary protein C, protein S, or antithrombin deficiency may be overdiagnosed, as these inhibitors are nonspecifically decreased in many affected childre