Vascular diseases of the liver

How can I be sure that the patient has vascular liver disease?

When should I consider vascular liver disease diagnosis?

Ischemic cholangiopathy

Ischemic cholangiopathy is characterized by diffuse or focal injury to large bile ducts resulting from an impaired arterial blood supply.

Diagnosis of ischemic cholangiopathy should be considered whenever there are anomalies of the large bile ducts occurring in the context of an intervention or a systemic disease known to impair the arterial blood supply to the bile ducts – or is likely to do so.

Budd-Chiari syndrome

Primary Budd-Chiari (BCS) is a rare disorder caused by thrombosis of the hepatic veins or the terminal portion of the inferior vena cava. Its estimated incidence ranges from 0.2 to 0.8 per million per year.

BCS presentation is highly heterogeneous with fulminant, acute, chronic, and asymptomatic forms. Given the absence of specific clinical or laboratory signs for BCS, this diagnosis should be widely considered in patients with acute or chronic liver disease.

Extrahepatic portal vein thrombosis

Extrahepatic portal vein thrombosis is characterized by a thrombus developed in the main portal vein, and/or its right or left branches, or by the permanent obliteration that results from a prior thrombus. The prevalence in population-based necropsy studies was about 1%, most of the cases being related to cirrhosis or to malignancy.

Acute portal vein thrombosis in the absence of cirrhosis

Currently, most patients are identified at this acute stage.

Main features:

• Sudden abdominal pain

• Systemic inflammatory response syndrome even in the absence of an abdominal focus of infection.

The contrast between severe pain and the lack of guarding is regarded as suggestive of acute portal vein thrombosis.

Chronic portal vein thrombosis in the absence of cirrhosis

This stage is characterized by the rapid development of portoportal collaterals bypassing the obstructed venous segment. These collaterals have also been called a portal cavernoma.

Diagnosis should be considered in patients with gastrointestinal bleedings related to portal hypertension, particularly when bleeding recurs, and/or in the absence of liver insufficiency.

Portal vein thrombosis in patients with cirrhosis

Clinical features of acute portal vein thrombosis are nonspecific in this setting, most cases being identified at routine ultrasound either at the time of a complication of cirrhosis or during surveillance for hepatocellular carcinoma.

Diagnosis should be considered in patients with cirrhosis, who are undergoing gastrointestinal bleedings related to portal hypertension.

Sinusoidal obstruction syndrome/veno-occlusive disease

Sinusoidal obstruction syndrome (SOS) (also named veno-occlusive disease) is characterized by a nonthrombotic obstruction of the sinusoids, which may extend to the central veins, in the absence of thrombosis or other underlying disorder of the hepatic veins.

Diagnosis should be considered when portal hypertension and liver dysfunction occur in a context of exposure to agents toxic to bone marrow progenitors and to sinusoidal endothelial cells.

Noncirrhotic portal hypertension

Noncirrhotic portal hypertension corresponds to several entities: obliterative portal venopathy, nodular regenerative hyperplasia, hepatoportal sclerosis, and incomplete septal cirrhosis. There is considerable overlap between these forms of noncirrhotic portal hypertension.

Diagnosis should be considered in patients with all of the following features:

• Severe portal hypertension, particularly with upper gastrointestinal bleedings

• Absence of liver insufficiency

• Absence of common cause for cirrhosis

A tabular or chart listing of features and signs and symptoms

Ischemic cholangiopathy

Two major presenting features:

• Latent with progressive cholestasis: elevated levels of serum alkaline phosphatase and gamma-glutamyltransferase

• Angiocholitis

Less common clinical presentation, at a later stage of the disease:

• Itching and jaundice

• Hepato-cellular failure

Differential diagnoses:

• Primary sclerosing cholangitis

• Diffuse cholangiocarcinoma

• Cholangitis related to IgG4 disease

The differentiation with these alternative diagnoses is easy in a context of intervention affecting hepatic arteries or known systemic vasculitis but is extremely difficult when this context is lacking. The association with inflammatory bowel disease or features of IgG4 disease should always be investigated.

Budd-Chiari syndrome

Most frequent signs and symptoms:

• Ascites (80%)

• Abdominal pain (60%)

• Esophageal varices (60%)

Other classical signs and symptoms:

• Lower extremity edema (40%)

• Dilated veins over body, trunk (40%)

• Fever (15%)

• Hepatic encephalopathy (10%)

• Jaundice (10%)

• Gastrointestinal bleeding (5%)

Asymptomatic BCS accounts for 20% of the cases.

Laboratory findings: Differential diagnosis: cirrhosis, difficult

• Serum aminotransferases and alkaline phosphatase can be normal or increased.

• Levels of serum albumin, serum bilirubin, and prothrombin can be normal or abnormal, and in some patients are markedly abnormal.

• The protein level in ascetic fluid varies from patient to patient. Ascites protein content above 3.0 g/dL and serum-ascites albumin concentration gradient above 1.1 g/dL are suggestive of BCS, cardiac disease, or pericardial disease.

• Serum creatinine level can be elevated, usually due to prerenal dysfunction.

Differential diagnoses:

• Constrictive pericarditis is the most challenging differential diagnosis because it closely mimics hepatic venous obstruction at liver histology and because this diagnosis can be missed at echocardiography.

• Sinusoidal obstruction syndrome (context, no hepatic vein obstruction)

• Congestion heart failure (echocardiography useful)

• Angiocholitis (bile duct obstruction, sepsis)

Extrahepatic portal vein thrombosis

Acute portal vein thrombosis in the absence of cirrhosis

Most frequent signs and symptoms:

• Abdominal pain (90%) of sudden onset or progressing over a few days, contrasting with the absence of guarding

• Fever (50%)

Other classical signs and symptoms:

• Small-volume ascites (33%)

• Clinical ascites (5%)

• Lumbar pain

• Occasionally, nonbloody diarrhea

Laboratory findings:

• Marked systemic inflammatory response is common in the absence of sepsis.

• Liver function is preserved.

• A transient, moderate increase in serum aminotransferases can be observed.

Differential diagnosis:

• Peritonitis

Chronic portal vein thrombosis in the absence of cirrhosis

Most frequent signs and symptoms:

• 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.

Other classical signs and symptoms:

• Biliary symptoms related to portal cholangiopathy (jaundice, biliary pain, cholangitis, cholecystitis, or pancreatitis)

• Ascites, rare

• Encephalopathy, rare

• Hepatopulmonary syndrome in about 10% of patients

Laboratory findings:

• Liver tests are typically normal.

• Coagulation factor levels can be moderately altered.

Portal vein thrombosis in patients with cirrhosis

Signs and symptoms: nonspecific in this setting

• Most cases being identified at routine ultrasound.

• Often accompanied by gastrointestinal bleeding, ascites, or encephalopathy

Differential diagnosis:

Neoplastic obstruction should always be considered, especially when:

• Serum alpha fetoprotein levels are increased;

• The portal vein is larger than 23 mm in diameter;

• Endoluminal material enhances during the arterial phase of contrast injection;

• An arterial-like pulsatile flow is seen on Doppler ultrasound

Needle biopsy of an obstructed intrahepatic portal vein is specific but relatively insensitive for diagnostic purposes.

Sinusoidal obstruction syndrome/veno-occlusive disease

Typical features:

• Weight gain

• Ascites

• Right upper quadrant abdominal pain

• Hepatomegaly

• Followed by the development of jaundice

Other classical signs and symptoms:

Clinical features vary from the absence of signs and symptoms to a severe hepatic dysfunction leading to multiorgan failure and death. Differential diagnosis:

The clinical diagnosis of SOS is a difficult one because confounding factors are numerous, particularly in the setting of myeloablative therapy:

• Viral hepatitis

• Toxicity of other drugs

• Graft versus host disease

• Sepsis

Noncirrhotic portal hypertension

Most frequent sign and symptom:

• Upper gastrointestinal bleeding

Other classical signs and symptoms:

• Ascites, uncommon except transiently after gastrointestinal bleeding

• Hepatic dysfunction, little or rare

• Encephalopathy, when present, is related to large portosystemic shunts.

• Asymptomatic forms, limited to isolated abnormal laboratory tests: 20% of obliterative portal venopathy patients

Differential diagnosis: cirrhosis, difficultFeatures that should raise a strong suspicion of noncirrhotic portal hypertension include:

• The absence of common causes for cirrhosis

• The contrast between severe portal hypertension and preserved liver function

• The context of extrahepatic disease, if any (see later section “Causes and risk factors for noncirrhotic portal hypertension”)

How can I confirm the diagnosis?

Ischemic cholangiopathy

What tests should be ordered first?

• Serum alkaline phosphatase, gamma-glutamyltransferase, aminotransferase, bilirubin, and albumin level

• Quick time

• C-reactive protein, blood count

What tests should be used to diagnose ischemic cholangiopathy?

• In all patients, magnetic resonance imaging of the liver, pancreas, and bile ducts: casts as filling defects, bilomas, or irregular large bile ducts. Predominance of the stenoses in the central portion of the biliary tree is suggestive but not specific for ischemic cholangiopathy.

• In the post-transplant setting, Doppler ultrasound: a sensitive procedure for assessing hilar hepatic arteries. Decreased hepatic arterial resistance indices suggests a stenosis or an occlusion, which will need confirmation with arterial reconstruction at CT scan.

• Outside the transplant setting, the evaluation of the large arteries with Doppler ultrasound or CT scan is much less informative because the disorder involves the peribiliary plexus, which is not accessible to radiological imaging.

Diagnostic algorithm:

See Figure 1 for a diagnostic algorithm for ischemic cholangiopathy.

Figure 1.

Budd-Chiari syndrome

What tests should be ordered first?

• Liver function tests

• Blood cell count

What tests should be used to diagnose BCS?

• BCS is diagnosed by the demonstration of an obstruction of the hepatic or inferior caval venous lumen, and/or by the presence of hepatic vein collaterals.

• Doppler ultrasound by an experienced examiner, aware of the diagnostic suspicion, is the most effective and reliable diagnostic means.

• Magnetic resonance imaging (MRI) and CT scan confirm the diagnosis, being most useful in the absence of an experienced Doppler ultrasound examiner.

What tests are useful if the diagnosis is still in doubt?

• Invasive procedures, such as liver biopsy and X-ray venography, are needed only in patients whose diagnoses remain uncertain after noninvasive imaging procedures.

• Biopsy usually brings nonspecific evidence for an impaired blood outflow, including congestion, coagulative necrosis, or simple loss of hepatocytes without inflammatory infiltrates, and/or fibrosis – all features predominating in the centrilobular area.

Extrahepatic portal vein thrombosis

What tests should be ordered first?

• Blood cell count

• C-reactive protein

What tests should be used to diagnose portal vein thrombosis?

• Liver function tests

• Doppler ultrasound

• CT scan

Findings in acute portal vein thrombosis in the absence of cirrhosis

At Doppler ultrasound: solid echoes within the portal vein or branches and the absence of flow are sufficient for the diagnosis. The limits of Doppler ultrasound as a diagnostic technique are related to patient’s body habitus, especially for the visualization of mesenteric veins, and to the lack of an examiner’s awareness or experience.

CT scan provides additional information regarding the extent of the thrombus to the mesenteric veins and arches, the dating of the thrombus, the presence of a local factor, or of congestion and ischemia of the bowel. Hyperattenuation of the portal vein lumen on unenhanced CT scan is found only in patients investigated within 30 days of the onset of symptoms.

Findings in chronic portal vein thrombosis in the absence of cirrhosis

• Serpiginous structures while the main portal vein and/or its main branches are not visible.

• 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.

Findings in portal vein thrombosis in patients with cirrhosis

• In most cases, the thrombus is partial and changes in aspect and location at follow-up imaging.

• No arterial enhancement of the thrombus

Sinusoidal obstruction syndrome/veno-occlusive disease

What test should be ordered first?

• Liver function tests

• Hepatitis A, B, and C markers

• Doppler ultrasound: gives unspecific information by showing heptomegaly, ascites, splenomegaly, periportal oedema but helps in ruling out biliary obstruction, infiltrative tumors, or infectious lesions such as liver abscess and hepatic or portal vein obstruction.

• CT scan: not recommended due to the toxicity of contrast agents.

What tests should be used to diagnose SOS?

Liver biopsy, when clinical and imaging information is not sufficient to make a diagnosis of SOS in patients with moderate or severe disease. In patients with low platelets or severe ascites, a transjugular route is usually preferred. Complication and mortality rates, related to this procedure have been 7% to 18% and 0% to 3%, respectively.

• A hepatic venous gradient (>10 mm Hg) is highly specific for SOS in a context of exposure to myeloablative therapy.

• Initial lesions consist of edematous subendothelial zone containing fragmented red cells and noncellular debris, with enlarged congestive sinusoids and perivenular hepatocyte necrosis.

• Later stages of SOS are characterized by extensive collagenization of sinusoids and venules, eccentric luminal narrowing, and phlebosclerosis.

• Nodular regenerative changes may represent a late sequella.

Noncirrhotic portal hypertension

What tests should be ordered first?

• Liver function tests

• Ruling out common causes for cirrhosis

• Doppler ultrasound: to rule out hepatic or portal vein obstruction

What tests should be used to diagnose noncirrhotic portal hypertension?

Liver biopsy:

• Obliterative portal venopathy is defined by a finding of abnormal small portal veins in the absence of cirrhosis. The anomalies consist of an absence of small portal veins or a clear reduction in their caliber, with sclerosis or thickening of the smooth muscle wall. Ectopic small vascular channels (mostly in the periportal area of the lobule), as well as an increased number of vascular channels in the portal tracts, constitute a hallmark for this entity. These abnormal portal veins should be observed in a high proportion of analyzed vessels because similar changes have been found in more than 25% of portal tracts in ‘‘normal livers with normal portal pressure.’’ These obliterations of the small portal veins are usually associated with portal fibrosis, nodular regenerative hyperplasia, and sinusoidal dilatation or fibrosis.

• Nodular regenerative hyperplasia is characterized by the diffuse development of thickened and irregularly oriented liver cell plates in the absence of significant portal or sinusoidal fibrosis. The areas of nodular parenchyma are separated by areas of compressed atrophic cell plates.

What other diseases, conditions, or complications should I look for in patients with vascular liver disease?

What are the major risk factors in patients with vascular liver disease?

Ischemic cholangiopathy

Main causes of ischemic cholangiopathy

• Liver transplantation

• Hepatic artery chemotherapy infusion

• Hepatic artery embolization or chemoembolization

• Radiotherapy on main bile duct area

• Cholecystectomy

• Hereditary hemorrhagic telangiectasia

• Systemic vasculitis/microangiopathy

• AIDS

• Recent history of intensive care

Budd-Chiari syndrome, portal vein thrombosis, and noncirrhotic portal hypertension

Prevalence of acquired and inherited risk factors for BCS, PVT, and cirrhotic portal hypertension in recent European cohort studies.

See Table I.

Table I.n

Local risk factors for portal vein thrombosisLocal risk factors:

• Cancer, any abdominal organ

• Focal inflammatory lesions

• Neonatal omphalitis, umbilical vein catheterization

• Diverticulitis, appendicitis

• Pancreatitis

• Duodenal ulcer

• Cholecystitis

• Tuberculous lymphadenitis

• Crohn’s disease, ulcerative colitis

• Cytomegalovirus hepatitis

Injury to the portal venous system:

• Splenectomy

• Colectomy, gastrectomy

• Cholecystectomy

• Liver transplantation

• Abdominal trauma

• Surgical portosystemic shunting, TIPS, liver transplantation

Cirrhosis:

• Preserved liver function with precipitating factors (splenectomy, surgical portosystemic shunting, TIPS dysfunction, thrombophilia)

• Advanced disease in the absence of obvious precipitating factors

Investigations for thrombotic risk factors in patients with vascular diseases of the liverMyeloproliferative neoplasm. V617FJAK2 mutation in peripheral granulocyte DNA. In patients testing negative, thrombopoietin receptor (MPL), and JAK2 exon 12 mutations. If further negative, consider bone marrow biopsy for demonstrating clusters of dystrophic megagaryocytes, particularly in patients with normal blood cell counts and splenomegaly. Paroxysmal nocturnal hemoglobinuria. Routinely CD55- and CD59-deficient clone at flow-cytometry of peripheral blood cells.Behcet’s disease. Diagnosis based on a set of conventional criteria. To be routinely considered in patients with inferior vena cava thrombosis, or originating from endemic areas, or having extrahepatic features suggestive of the disease. Antiphospholipid syndrome. Diagnosis based on repeatedly detectable anticardiolipin antibodies at high level, or lupus anticoagulant, or antibeta2 glycoprotein 1 antibodies. Many patients with vascular liver disease have nonspecific fluctuating, low titer antiphospholipid antibodies in the absence of antiphospholipid syndrome.Factor V Leiden. Activated protein C resistance. To be confirmed in patients with positive results by molecular testing for R605Q factor V mutation.Factor II gene mutation. Molecular testing for G20210A mutation. Primary antithrombin deficiency. Results can be interpreted only in patients with normal coagulation factor levels. Diagnosis based on decreased antithrombin activity levels. Inherited deficiency can be established only with a positive test in first-degree relatives.Primary protein C deficiency. Results can be interpreted only in patients with normal coagulation factor levels. Diagnosis based on decreased protein C activity levels. Inherited deficiency can be established only with a positive test in first-degree relatives.Primary protein S deficiency. Results can be interpreted only in patients with normal coagulation factor levels. Diagnosis based on decreased free protein S levels. Inherited deficiency can be established only with a positive test in first-degree relatives.Hyperhomocysteinemia. Increased serum homocysteine level prior to disease. Uncertain value of C677T homozygous polymorphism. In many patients, a definite diagnosis for underlying hyperhomocysteinemia will not be possible. Blood folate and serum vitamin B12 levels may be useful.Celiac disease. Antitransglutaminase autoantibodies. HIV infection. Anti-human immunodeficiency virus antibodies.Oral contraceptives and pregnancies. Medical history.Inflammatory condition. Increased circulating levels of C reactive protein or fibrinogen levels. Increased platelet counts

Drugs and agents implicated in sinusoidal obstruction syndrome/veno-occlusive disease

• Plants containing pyrrolizidine alkaloids consumed either as contaminated flour or as traditional or herbal remedies

• High-dose radiotherapy to the liver

• Exposure to certain toxic agents: azathioprine and its derivatives, actinomycin D, busulfan, cytosine arabinoside, cyclophosphamide, dacarbazine, gemtuzumab-ozogamicin, melphalan, oxaliplatin, urethane

Causes and risk factors for noncirrhotic portal hypertension

• Shistosoma mansoni or japonicum, worldwide, the leading cause

• Chronic exposure to various chemicals (arsenic, copper sulfate, vinyl chloride, thorium dioxide) or drugs (azathioprine)

• Underlying prothrombotic conditions in up to 50% of patients. Therefore, risks factors for thrombosis should be routinely screened in all patients with suspected noncirrhotic portal hypertension.

• Immune-mediated disorders such as thyroiditis, systemic lupus, Sjögren syndrome, autoimmune hepatitis, and primary biliary cirrhosis

• Systemic diseases: sarcoidosis, common variable immunodeficiency, and HIV

• Familial occurrence or association with congenital diseases (Turner syndrome, Adams-Oliver syndrome)

What are the complications of vascular disease?

Ischemic cholangiopathy

• Angiocholitis with potentially severe septic shock

• Hepato-cellular failure

Budd-Chiari syndrome

• Gastrointestinal bleeding

• Ascites and related under-nutrition

• Spontaneous bacterial peritonitis

• Liver insufficiency

• Hepatocellular carcinoma. (See Figure 2.)

• Outcome of the underlying diseases. By 12 years of follow-up, myelofibrosis or acute leukemia has been reported to occur in up to 30% of patients with myeloproliferative neoplasms and splanchnic vein thrombosis

Figure 2.

Portal vein thrombosis

• Gastrointestinal bleeding

• Outcome of the underlying diseases (see above: Budd-Chiari syndrome/outcome of underlying diseases)

• Intestinal infarction: the most dreaded complication of portal vein thrombosis. Its mortality is currently 20% to 60%, and severe disability may result from either extended resection or post-ischemic intestinal stenoses. Intestinal infarction has been reported in 2% to 28% of patients with acute portal vein thrombosis.

Ischemia or infarction should be strongly suspected in patients with persisting intense pain despite adequate anticoagulation, hematochezia, guarding, contracture, ascites, or multiorgan failure with metabolic acidosis. A CT scan with and without vascular enhancement should be obtained urgently. A suspicion for bowel ischemia should be raised by the following focal aspects: homogeneous or heterogeneous hypoattenuating or hyperattenuating wall thickening, dilatation, abnormal or absent wall enhancement, mesenteric stranding, and also ascites, pneumatosis, and portal venous gas. Diffuse homogeneous wall thickening is probably more suggestive of congestion related to acute portal hypertension than of ischemia in this context of venous thrombosis. Decreased wall enhancement and dilatation of the lumen have been proposed as criteria for differentiating transmural infarction from nontransmural ischemia.

Sinusoidal obstruction syndrome/veno-occlusive disease

• Multiorgan failure

Noncirrhotic portal hypertension

• Gastrointestinal bleeding

• Portal vein thrombosis

What is the right therapy for the patient with vascular liver disease?

What is the right therapy for the patient with ischemic cholangiopathy?

Treatment has to be individualized, based on the presence or absence of symptoms, time from arterial injury and acute or chronic type of lesions, location of the predominant biliary anomalies, and context. (See Figure 1.) Causal factors:

• Hepatic artery stenosis/thrombosis: thrombolysis, stenting, reconstruction

• Systemic vasculitis: anticoagulation/antiplaletet agents? Immunosuppressive therapy?

Collections:

• Percutaneous drainage

Casts and stones:

• Sphincterotomy

• Nasobiliary or

• Percutaneous drainage

Strictures:

• Balloon dilatation

• Stenting

• Reconstruction

Liver failure:

• Recurrent bacterial cholangitis: consider liver transplantation.

In the particular post-transplant setting:

• Early hepatic artery occlusion or stenosis should be treated with emergency re-intervention and arterial reconstruction.

• Delayed hepatic artery obstruction justifies arteriography and, if appropriate, percutaneous dilatation and stenting.

What is the right therapy for the patient with Budd-Chiari syndrome?

First step in all patients:

Treat ascites, gastrointestinal bleeding, bacterial infection, renal dysfunction, and encephalopathy as recommended for cirrhosis. (See Figure 3.)

Figure 3.

Give specific state-of-the-art therapy for underlying prothrombotic conditions (e.g., myeloproliferative disease, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, Behcet’s disease).

Initiate anticoagulation as soon as the diagnosis has been established and after prophylaxis for bleeding related to portal hypertension has been instituted.

• Prefer low molecular weight heparin to unfractionated heparin unless there is a need for immediate cessation of anticoagulation.

• Closely monitor for heparin-induced thrombocytopenia. Give daparanoid sulfate as an alternative.

• Target anti-Xa level at 0.5 IU/mL.

• When this level cannot be achieved with usual doses, check for primary or secondary deficiency in antithrombin and give recombinant antithrombin as appropriate.

• Substitute heparin for permanent oral anticoagulation as soon as invasive therapy is deemed not required.

• Target an INR 2 to 3 or, preferably a factor II level of 25% to 35%.

• Preferably refer the patient to an anticoagulation clinic.

Second step:Check for short-length stenosis of inferior vena cava or hepatic veins using percutaneous angiography, if needed, and treat appropriately with angioplasty, with or without stenting.

Third step:

When the patient fails to improve steadily with the previous measures, proceed to transjugular intrahepatic portosystemic shunt (TIPS) insertion, usually through the transcaval route.Fourth step:When TIPS insertion fails or the patient does not improve or he/she develops chronic or recurrent encephalopathy, consider liver transplantation.

What is the right therapy for the patient with portal vein thrombosis?

Acute portal vein thrombosis

See Figure 3.

Check for the presence of a local factor and an underlying prothrombotic condition and consider correcting these factors as soon as possible.

In the absence of active bleeding, initiate anticoagulation as soon as the diagnosis has been established.

Prefer low molecular weight heparin to unfractionated heparin unless there is a need for immediate cessation of anticoagulation.

• Closely monitor for heparin-induced thrombocytopenia. Give daparanoid sulfate as an alternative:

• Target antiXa level at 0.5 IU/ml.

• When this level cannot be achieved with usual doses, check for primary or secondary deficiency in antithrombin and give recombinant antithrombin as appropriate.

Substitute heparin for oral anticoagulation as soon as invasive therapy is deemed not required.

• Maintain anticoagulation therapy for 3 to 6 months.

• Target INR 2 to 3 or, preferably, factor II level at 25% to 35%.

• Preferably refer the patient to an anticoagulation clinic.

Consider permanent anticoagulation:

• In patient with a strong underlying prothrombotic disorder that cannot be corrected

• In patients who have superior mesenteric vein thrombosis

Portal cavernoma

See Figure 3.

Screen and initiate prophylaxis for bleeding from portal hypertension as recommended for cirrhosis.

Consider permanent anticoagulation once prophylaxis has been instituted:

• In the patient with a strong underlying prothrombotic disorder that cannot be corrected

• In the patients with thrombosis of the superior mesenteric vein

Portal vein thrombosis in patients with cirrhosis

See Figure 3.

Anticoagulation. Whether or not anticoagulation should be given to patients with cirrhosis and portal vein thrombosis remains debated. There are reports of successful recanalization with anticoagulation in selected patients, particularly those listed for liver transplantation. TIPS

• When a TIPS is otherwise indicated, results on portal vein thrombosis are good.

• Whether or not the mere development of a portal vein should prompt the insertion of a TIPS is less clear.

Enoxaparin.Recent data reported in a preliminary form indicate that enoxaparin administration may prevent the development of portal vein thrombosis and decrease the incidence of complications in patients with cirrhosis of intermediate severity (Child Pugh score B7 to C10).

What is the right therapy for the patient with noncirrhotic portal hypertension?

There is a lack of solid data on treatment for noncirrhotic portal hypertension.

Prevention and management of variceal bleeding can probably be performed according to the same guidelines as those for cirrhosis:

• Beta-blockers and/or endoscopic therapy for the prevention of bleeding

• Endoscopic therapy associated with vasoactive drugs for the treatment of acute variceal bleeding

TIPS placement could be considered in case of failure to control variceal bleeding.Anticoagulation therapy may be useful in patients with noncirrhotic portal hypertension and underlying prothrombotic conditions. Indeed, extrahepatic portal vein thrombosis can be associated with noncirrhotic portal hypertension at diagnosis and frequently develops during the follow-up of noncirrhotic portal hypertension, particularly in patients with underlying prothrombotic conditions (77% of such patients).

Liver transplantation is required in up to 15% of the patients due to liver failure, often after an acute event, or hepatopulmonary.

What is the right therapy for the patient with sinusoidal obstruction syndrome (veno-occlusive disease of the liver)?

Prevention. In a context of hematopoietic stem cell transplantation, patients at high risk for severe toxic liver injury should be identified prior to myeloablative regimens in order to adapt the latter. The indicators include preexisting extensive hepatic fibrosis, viral hepatitis, nonalcoholic or alcoholic hepatitis, myelofibrosis with extramedullar hematopoiesis, recent treatment with gemtuzumab, or a previous history of SOS. Regimens that are less liver toxic include reduced intensity regimens, regimens without cyclophosphamide, and regimens with lower doses of total body irradiation, below 12Gy. However, the advantages of preventing SOS in the short term should be weighed against an increased short- and long-term risk of graft versus host disease and an increased long-term risk of a poor control of the underlying malignancy.

Defribrotide.This treatment has shown a benefit in preventing SOS in a randomized study in children and in a nonrandomized, historical controlled study. More data are needed to make a definitive opinion on the utility of this treatment whose main advantage might be a good safety profile.

Studies on heparin, ursodeoxycholic acid, and prostagandin E1. These studies gave mixed results.

Pharmacological thrombolysis.This treatment is not recommended.

TIPS.This treatment was associated with a 50% immediate mortality rate and a delayed mortality of 40%.

Data on liver transplantationin this setting are anecdotal.

How should I monitor the patient with vascular liver disease?

In all patients with stabilized vascular liver disorders:

• Liver function tests twice a year

• Ultrasonography for assessment of extension or development of thrombosis twice a year

• Close monitoring for anticoagulation

• If there is an underlying prothrombotic condition, the patient should also be followed by a hematologist.

In patients with Budd-Chiari syndrome: screening twice a year for hepatocellular carcinoma (Figure 2).

What's the evidence?

Cazals-Hatem, D, Hillaire, S, Rudler, M. “Obliterative portal venopathy: portal hypertension is not always present at diagnosis”. J Hepatol. vol. 54. 2011. pp. 455-61. (This recent retrospective study included 59 patients with obliterative portal venopathy and described the clinical features, risk factors, and outcome of these patients.)

Darwish Murad, S, Plessier, A, Hernandez-Guerra, M. “Etiology, management, and outcome of the Budd-Chiari syndrome”. Ann Intern Med. vol. 151. 2009. pp. 167-75. (This reference is the first prospective multicentric study in Budd-Chiari syndrome. This series included 163 patients and characterized the causes and treatment of Budd-Chiari syndrome.)

de Franchis, R. “Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension”. J Hepatol. vol. 53. 2010. pp. 762-8. (This reference is the recent European consensus on portal hypertension.)

DeLeve, LD, Valla, DC, Garcia-Tsao, G. “Vascular disorders of the liver”. Hepatology. vol. 49. 2009. pp. 1729-64. (This reference is the guideline of the American Association for the Study of the Liver on the vascular disorders of the liver.)

Deltenre, P, Valla, DC. “Ischemic cholangiopathy”. Semin Liver Dis. vol. 28. 2008. pp. 235-46. (This review article is a comprehensive overview of the mechanisms leading to ischemic cholangiopathy.)

Francoz, C, Belghiti, J, Vilgrain, V. “Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation”. Gut. vol. 54. 2005. pp. 691-7. (This retrospective study assessed the prevalence of and risk factors for splanchnic vein thrombosis in a cohort of 251 cirrhotic patients listed for transplantation and assessed the usefulness of anticoagulation.)

Plessier, A, Darwish-Murad, S, Hernandez-Guerra, M. “Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study”. Hepatology. vol. 51. 2009. pp. 210-8. (This reference is the unique prospective multicentric study in acute portal vein thrombosis. This series included 102 patients and prospectively assessed the risk factors, outcome, and prognosis in patients with acute portal vein thrombosis treated with early anticoagulation

Delgado, MG, Seijo, S, Yepes,, I. “Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis”. Clin Gastroenterol Hepatol. vol. 10. 2012. pp. 776-83. (This reference is a retrospective observational cohort study describing the effects of anticoagulation therapy for portal vein thrombosis in 55 patients with cirrhosis.)

Siramolpiwat, S, Seijo, S, Miquel, R. “Idiopathic portal hypertension: natural history and long-term outcome”. Hepatology. vol. 59. 2014. pp. 2276-85. (This reference is a long term follow-up study of a cohort of patients with idiopathic noncirrhotic portal hypertension describing the incidence of complications on prophylaxis for gastrointestinal bleeding.)

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