Aetiology

An underlying risk factor for thrombosis is found in up to 87% of patients with Budd-Chiari syndrome (BCS). A combination of several causal factors is demonstrated in about 25% of patients when investigated.[1]​

Seventy-five percent of patients with BCS have at least one hypercoagulable state (hereditary or acquired) as a predisposing factor.[1]​

  • A myeloproliferative disorder is the main pro-coagulant disorder in 50% of patients.[19] Polycythaemia vera is found in 10% to 40% of patients, whereas essential thrombocythaemia and myelofibrosis are less prevalent causes.[20][21]​ Mutations within the Janus Kinase 2 (JAK2) or thrombopoietin receptor gene (MPL) that are linked to myeloproliferative disorders may also predispose to liver thrombosis.[22][23]

  • Thrombophilic disorders are the next most frequent causes of BCS. Factor V Leiden mutation is present in around 30% of patients.[19] Other inherited thrombophilic disorders include prothrombin factor mutation, methylenetetrahydrofolate reductase mutation, protein C and S deficiency, antithrombin III deficiency, plasminogen deficiency, and TT677 MTHFR genotype.[20][24]

  • Other causes include paroxysmal nocturnal haemoglobinuria (12% of patients), antiphospholipid syndrome, hyperhomocysteinaemia, Behcet's syndrome, hypereosinophilic syndrome, granulomatous venulitis, and ulcerative colitis.[1]​[25][26]​​​​

  • The use of oral contraceptives in relation to heterozygosity or homozygosity for thrombophilic defects is considered a risk factor for BCS.[27][28][29]

  • Pregnancy and immediate post-partum period are associated with hormonal changes, inferior vena cava (IVC) compression, and physiological hyperfibrinogenaemia, which predispose to BCS.[6]

  • The cause of IVC thrombosis may be a hypercoagulable state such as coagulation factor deficiency and myeloproliferative disorders, but is more often idiopathic. In Asian countries, IVC thrombosis has been associated with infections.[1][16]​​

  • There appears to be a predominance of obstruction at the level of the suprahepatic IVC in children. The aetiology remains unclear as underlying prothrombotic diseases have not been routinely investigated. There are; however, isolated case reports of an association with factor V Leiden or prothrombin gene mutation, antiphospholipid syndrome, or coeliac disease.[1]​​

Secondary BCS may result from external compression or invasion of the venous lumen by abscess, tumours, trauma, or cysts. Large nodules of focal nodular hyperplasia in a central location may cause compression of the hepatic veins. Compression or kinking of the hepatic veins can occur following hepatic resection or transplantation. BCS may occur following blunt abdominal trauma, either from compression by intrahepatic haematoma, IVC thrombosis related to trauma, or herniation of the liver through a ruptured diaphragm.​[1]

In about 10% of patients with BCS, an underlying aetiology cannot be identified.[24]

Pathophysiology

Hepatic venous outflow obstruction gives rise to several haemodynamic changes. In the early stages of the disease there is concomitant decrease in portal perfusion, which leads to portal venous thrombosis and compensatory increase in arterial perfusion.[30] Decreased sinusoidal blood flow and increased sinusoidal pressure can eventually lead to portal hypertension. The resulting venous congestion provokes ischaemic damage and necrosis of adjacent hepatocytes. Hypoxia also stimulates the release of free radicals from sinusoidal lining cells that further contribute to oxidative hepatocyte injury.[31]

Primary thrombosis of the IVC, also known as obliterative hepatocavopathy, occurs most commonly in its hepatic portion or in the suprahepatic portion. It is also called membranous obstruction of IVC, because the thrombus organises into a fibrous and frequently membranous occlusion of the IVC.[16]

Classification

Aetiological classification[3]

Primary

  • Venous obstruction occurs as a result of a primarily venous disease such as thrombosis, phlebitis, stenosis, or webs.

Secondary

  • Caused by external compression or invasion of the venous lumen by abscess, tumours, or cysts.

Anatomical classification[4]

Four disease types according to the site of venous obstruction and the presence or absence of portal vein thrombosis (PVT):

  • Single hepatic vein obstruction or thrombosis without PVT

  • Single hepatic vein obstruction or thrombosis with PVT

  • Isolated webs of hepatic vein and IVC

  • Multiple hepatic vein thromboses with compression/thrombosis of the IVC and PVT

Clinical classification[5]

Based on the severity of presentation and duration of symptoms:

  • Asymptomatic: no ascites or abdominal pain; diagnosed following investigation of slightly abnormal results in liver function tests

  • Acute/subacute (hepatic necrosis without the formation of venous collaterals): right hypochondrial pain, hepatomegaly, and intractable ascites; short duration of symptoms

  • Chronic: manifests as complications of cirrhosis

  • Fulminant (uncommon): hepatic encephalopathy within 8 weeks after the development of jaundice; tender and enlarged liver; renal failure and coagulopathy are also commonly seen

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