Portal vein thrombosis (PVT) is one cause of extrahepatic portal venous obstruction characterized by the obliteration of the portal vein supply leading to portal hypertension. Acute or chronic PVTs are successive stages of the same disease. In the absence of recanalization, porto-portal collaterals develop, leading to a portal cavernoma. Although they share similar causes, the clinical presentation and management differs.[1, 2] Portal vein obstruction in patients with cirrhosis, secondary to hepatocarcinoma invasion or congenital malformation of the portal vein, constitutes distinct entities. Although noncirrhotic nontumoral PVT (NCPVT) is a rare disease, it is the second most common cause of portal hypertension in the world.
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A risk factor is identified in up to 70% of patients (Table 1). A systemic prothrombotic factor is identified in ∼60% of these cases, and a local factor is documented in 20%-40% of cases.[1-6] In over 15% of patients, multiple etiologic factors coexist1,2; therefore, a complete etiological study is required even after a prothrombotic or local factor has been identified (Table 2). Despite this, NCPVT still remains idiopathic in up to 30% of patients.
The clinical manifestations of NCPVT depend on whether the condition is acute or chronic.
The main complaints of acute NCPVT are abdominal or lumbar pain associated with systemic inflammatory response syndrome. Ascites is present in 40% of patients but is usually only visible on imaging. Persistent severe abdominal pain despite adequate anticoagulation, organ failure, metabolic acidosis, abundant ascites, rectal bleeding, and abdominal contracture, especially in patients with diabetes, appear to be suggestive for infarction. Although the incidence of intestinal infarction has been reduced due to great strides made in early diagnosis and anticoagulation, its rapid recognition is important to avoid extensive bowel resection.[1, 7]
Chronic NCPVT (Cavernoma)
Portal hypertension–related complications are the main clinical features of chronic NCPVT.[1, 2, 8] Variceal bleeding is the most frequent manifestation, but its related mortality is much lower than in patients with cirrhosis.[1, 2] Gastroesophageal varices may develop early. Ectopic varices (i.e., duodenum, anorectal region, and gallbladder bed) are more frequent in NCPVT patients than in those with cirrhosis, whereas portal hypertensive gastropathy is rare. Ascites is quite infrequent and is usually associated with triggering events such as gastrointestinal bleeding or infection.[1, 2] Although overt encephalopathy is rare, half of patients may develop minimal hepatic encephalopathy.
Portal cholangiopathy is defined as abnormalities in the biliary tree by compression and deformation of intrahepatic and extrahepatic bile ducts by the collateral veins of the cavernoma.[1, 9, 10] Although 80% of patients with long-standing NCPVT have radiological biliary alterations, liver tests are generally only mildly abnormal (and most commonly reveal cholestasis). Clinical manifestations are infrequent, with severe and life-threatening complications (e.g., cholecystitis, cholangitis, obstructive jaundice) occurring in only 5%-35% of patients.[1, 2]
Color Doppler ultrasound is the initial technique used to assess portal vein patency. Computed tomography and magnetic resonance angiography provide additional information, such as the presence of associated local factors. Table 3 describes the radiological features that may help a diagnosis of acute or chronic NCPVT, and benign or malignant nature of PVT, which may not be easily distinguishable sometimes. Magnetic resonance cholangiography is the technique of choice to assess portal cholangiopathy. Liver biopsy, and in our experience FibroScan, can be useful to rule out an underlying chronic liver disease.
The treatment goals are to recanalize the thrombosed veins, to prevent the development of both intestinal infarction and portal hypertension, and to correct any underlying local or systemic factor. Although no randomized controlled trials have been performed, anticoagulation is recommended because spontaneous recanalization of the thrombosed vessel is a rare event.[1, 3, 11] On anticoagulation, partial or complete recanalization may occur in 40% and 50%, respectively. Early anticoagulation may significantly improve recanalization (60% if started within the first week after the diagnosis versus 20% if started later). The initial extent of thrombosis, the presence of ascites, and the presence of several prothrombotic disorders are negative predictive factors for recanalization. The optimal length of anticoagulation has not been determined. Portal vein recanalization may be expected to occur up to 4–6 months after starting anticoagulation, though the mesenteric and splenic veins may recanalize even later. Therefore, it is advisable to keep patients on anticoagulation for at least 6 months (table 4). Low molecular weight heparins, switched to acenoumarol or warfarin, are used. Major complications of anticoagulation therapy are low. Experience of thrombolysis and transjugular intrahepatic portosystemic shunt (TIPS) in this setting is scarce. The current literature suggests that recanalization rates with thrombolytic therapy are similar to that with anticoagulation alone, but with a much higher mortality and complications rate.[1, 8] Intestinal infarction requires emergent surgery to remove necrotic bowel.
The treatment aims are to prevent and treat complications of portal hypertension, to prevent recurrent thrombosis, and to treat portal cholangiopathy. Anticoagulation has been shown to prevent the progression and recurrence of thrombosis without increasing the risk or severity of gastrointestinal bleeding if adequate primary or secondary prophylaxis of variceal bleeding is adopted.[1, 4] Long-term anticoagulation is recommended in selected patients (Table 4). Treatment of portal hypertension complications are currently managed as they are for cirrhosis.[1, 2, 8] A recent study in patients with noncirrhotic portal hypertension (extrahepatic portal venous obstruction and noncirrhotic portal fibrosis patients) showed that endoscopic variceal ligation was not superior to propranolol for secondary prophylaxis. TIPS or surgical shunts can be considered for those patients with portal hypertensive bleeding with medical and endoscopic therapy failure. TIPS has poor success insertion rates and requires the patency of intrahepatic portal vein branches. Feasibility of surgical shunts depends on the splenic or mesenteric vein patency. Esophageal transection or splenectomy with variceal ligation is ineffective with a high frequency of late rebleeding due to reappearance of the varices. Rex shunt (mesenteric vein to left portal branch shunt) shows excellent results in children, but the experience in adults is still limited.
|Acquired prothrombotic diseases|
|• Myeloproliferative neoplasmsa (20%-28%)• Antiphospholipid syndrome (5%-19%)• Paroxysmal nocturnal hemoglobinuria (0%-2%)• Hyperhomocysteinemia (11%-22%)• Elevated factor VIII|
|Inherited prothrombotic diseases|
|• Factor V Leiden mutation (3%-9%)• Protein C deficiency (0%-10%)• Protein S deficiency (0%-30%)• Antithrombin deficiency (0%-5%)• Prothrombin G20210A mutation (3%-40%)• C677T MTHFR gene mutations (11%-50%)|
|• Abdominal inflammation: pancreatitis, diverticulitis, cholecystitis, appendicitis, inflammatory bowel disease, cytomegalovirus hepatitis, neonatal omphalitis • Umbilical vein catheterization • Abdominal trauma • Abdominal surgery|
|• Oral contraceptives (12%)b• Pregnancy, puerperium (6%-40%)b• Behçet disease • Celiac disease • Human immunodeficiency virus infection|
|Prothrombotic Disease||Recommended Test|
|Myeloproliferative neoplasmsa||JAK2V617F mutation, bone marrow biopsy; erythropoietin levels, endogenous erythroid colonies in cultures if previous tests are negative|
|Antiphospholipid syndrome||Repeatedly positive determinations of anticardiolipin antibodies, lupus anticoagulant or anti-β2 glycoprotein 1 antibodies|
|Paroxysmal nocturnal hemoglobinuria||Flow cytometry: presence of CD55- and CD59-deficient clone|
|Antithrombin, protein C, protein S deficiencies||Plasma levels of antithrombin, protein C, and protein S and their relation to factors II, V, VII, or X; study of family members; be aware of a possible vitamin K deficiency|
|Factor V Leiden mutation||Protein C-activated resistance or molecular analysis of R605Q mutation|
|G20210A prothrombin gene mutation||Molecular analysis of the G20210A mutation|
|Hyperhomocysteinemia||Serum homocysteine levels; blood folate and serum vitamin B12 levels may be evaluated|
|MTHFR gene mutation||Molecular analysis of C677T polymorphism|
|Recent surgery||Clinical criteria|
|Abdominal inflammation||Clinical criteria|
|Abdominal infection||Clinical criteria|
|• High luminal density in the thrombosed vessel at unenhanced phase • Lack of significant porto-portal collaterals • Features associated with intestinal resection: bowel or mesentery anomalies and distal thrombosis (occlusion of second order radicles of superior mesenteric vein)• Normal spleen size (although up to 40% of patients may have splenomegaly due to myeloproliferative neoplasm)|
|Chronic NCPVT (portal cavernoma)|
|• Portal cavernoma/portosystemic collaterals • Splenomegaly • Altered liver architecture and areas of nodular regenerative hyperplasia in relation to altered hepatic perfusion • Biliary tree abnormalities, biliary dilatation|
|• Intrathrombus signals with arterial waveforms • Neovascularity within PVT on contrast-enhanced ultrasound • Portal vein diameter ≥23 mm • Visible hypervascular tumor next to the obstruction|
|• Confirm thrombosis with radiologist, including extension and presence of local cause; exclude cirrhosis and malignant invasion • Immediate anticoagulation for at least 6 months • Close monitoring for possible mesenteric infarction; discuss intestinal resection when suspected • Thrombolysis is not recommended due to high mortality and complications • Consider long-term anticoagulation in patients with underlying prothrombotic disorder, recurrent thrombotic episodes, previous intestinal ischemia, or a family history of deep venous thrombosis • Screen for causes; specific management of underlying hematological diseases (i.e., MPN, PNH)• Varices screening (upper endoscopy within the first 2–3 months following the onset of acute NCPVT; if negative, repeat 6–12 months after and at 2- to 3-year intervals thereafter)• Management of portal hypertension (as in cirrhosis)|
|• Consider long-term anticoagulation in patients with underlying prothrombotic disorder, recurrent thrombotic episodes, previous intestinal ischemia, or a family history of deep venous thrombosis • Specific management of underlying hematological diseases (i.e., MPN, PNH)• Management of portal hypertension (as in cirrhosis)• MRC to assess presence and grade of portal cholangiopathy • TIPS or surgical shunts should be evaluated in patients with refractory portal hypertensive bleeding and failure to medical/endoscopic therapy, and patent portal branches. Risk of shunt thrombosis|
|• Ursodeoxycholic acid if cholestasis in blood tests or symptomatic portal cholangiopathy • ERCP (with or without sphincterotomy, stone removal, biliary stent) if symptomatic biliary strictures or choledocholithiasis • Portosystemic shunt in select severe cases with recurrent cholangitis associated with biliary strictures • Biliointestinal bypass should be avoided (high rates of morbidity and mortality)|
Recommendations are based on personal experience and retrospective series. Ursodeoxycholic acid is frequently used in patients with cholestasis or symptomatic portal cholangiopathy. Endoscopic retrograde cholangiography–driven therapy should be reserved for symptomatic biliary strictures or choledocholithiasis. In selected severe cases with recurrent cholangitis associated with biliary strictures, portosystemic shunt is the best treatment, since it reduces the risk of bleeding and decompresses the collaterals. Biliointestinal bypass has high rates of morbidity and mortality.[1, 2, 8] Liver transplantation is anecdotic in this setting.
Outcome of acute NCPVT is good with prompt diagnosis and treatment prior to intestinal infarction. Patency or recanalization of the mesenteric vein will prevent intestinal infarction. Recanalization of the portal vein and at least one of its branches will prevent portal hypertension. Overall mortality is <5% in recent series, mainly due to postoperative complications or the predisposing condition.
The outcome of portal cavernoma is relatively good and largely related to age, myeloproliferative neoplasms transformation into leukemia, myelofibrosis, and other unrelated diseases. Fewer than 5% of patients die due to gastrointestinal bleeding or intestinal infarction within 5 years.
Extrahepatic Portal Vein Occlusion in Children
Extrahepatic portal vein obstruction in children may not always be a result of thrombosis. The reported prevalence of an underlying prothrombotic disorder is high in most studies, although this is highly variable and myeloproliferative neoplasms have not been widely assessed in this population. Umbilical cannulation, omphalitis, and abdominal infections are common factors. However, the role of a properly placed, uninfected umbilical catheter in the absence of underlying thrombophilia is probably minimal. It is unclear whether growth retardation occurs in the absence of recurrent bleeding. Regarding management, anticoagulation has rarely been considered in this group of patients and endoscopic band ligation of esophageal varices may be the optimal therapy to prevent first bleed or recurrent bleeding. Mesenteric-to-left portal vein bypass (Rex shunt) has been reported with good results in terms of feasibility, prevention of rebleeding, restoration of portal inflow and hepatic function and improvement in cognitive function. Other shunts with the splenic or mesenteric vein, when available, have achieved good results. Outcome may be mostly jeopardized by cholangiopathy and minimal chronic hepatic encephalopathy in patients whose recurrent bleeding is well controlled with endoscopic therapy.
noncirrhotic nontumoral portal vein thrombosis
portal vein thrombosis
transjugular intrahepatic portosystemic shunt.