Hepatic Veno-occlusive Diseases

Sinusoidal Obstruction Syndrome

Sinusoidal obstruction syndrome (SOS) (formerly known as hepatic veno-occlusive disease [VOD]) is a toxin-induced, usually iatrogenic, vascular hepatic disorder. Previously thought to require the involvement of the hepatic venules, it is now recognized that SOS primarily afflicts the sinusoids and may spare the hepatic venules.

SOS was first linked to the ingestion of pyrrolizidine alkaloids in teas from Senecio, Heliotropium, and Crotalaria, sometimes resulting in epidemics of SOS in developing areas. In the West, SOS occurs almost exclusively in patients with cancer as a complication of chemotherapy and abdominal irradiation. Several chemotherapeutic and immunosuppressive agents have been implicated, but the most serious cases of SOS develop after hematopoietic stem cell transplantation with myeloablative conditioning. In patients undergoing stem cell transplant, the risk for developing SOS includes a history of prior stem cell transplantation, hepatitis C infection with elevated levels of aminotransaminases, underlying hepatic fibrosis or cirrhosis, advanced age, and infection at the time of transplant. Although controversial, there is no convincing evidence to support causation by thrombosis secondary to clotting and hypercoagulable states.

Budd-Chiari Syndrome

Budd-Chiari syndrome (BCS) refers to postsinusoidal obstruction at any level, from the small hepatic veins to the junction of the inferior vena cava (IVC) with the right atrium. Mechanical obstruction can be either primary or secondary. In primary BCS, the obstruction arises from the venous wall (fibrosis or phlebitis) or lumen (thrombosis). In secondary BCS, the obstruction originates from outside the vein and may be caused by extrinsic compression (abscess, cyst, or solid tumor) or tumor invasion.

Intravascular thrombosis is the most common mechanism of hepatic venous obstruction in primary BCS; at least one acquired or inherited procoagulative disorder is identified in up to 75% of patients. Acquired myeloproliferative disorders, such as polycythemia vera and, less commonly, essential thrombocythemia and myelofibrosis, account for 50% of cases of BCS. In the majority of cases, BCS is the initial manifestation of the underlying myeloproliferative disorder. Other acquired procoagulative states include paroxysmal nocturnal hemoglobinuria, malignancy, anti–phospholipid antibody syndrome, Behçet's disease, pregnancy, and oral contraceptive use. The most common inherited procoagulative disorder is factor V Leiden deficiency, occurring in up to 30% of cases of BCS. Other inherited states result in elevations of prothrombin, factors VII and VIII, and homocysteine and in deficiencies of antithrombin, protein C, and protein S.

Secondary BCS is sometimes seen when a malignant tumor grows within the lumen of its associated venous outflow tract (hepatocellular carcinoma [HCC], renal cell carcinoma, Wilms' tumor, and hepatic angiosarcoma). It also can result from extrinsic compression by malignant and benign solid tumors of the liver or adjacent organs, intrahepatic hematomas, hepatic abscesses, hydatid cysts, and hepatic cysts in polycystic kidney disease. No precipitating cause is identified in 10% of cases of BCS.

Sinusoidal Obstruction Syndrome

The inciting event in SOS is toxin-mediated sinusoidal endothelial injury. The injured endothelial cells undergo a morphologic transformation from their normal spindle shape to a rounder configuration, which narrows the sinusoidal lumen and introduces gaps between the cells. Blood flows through the gaps into the space of Disse, detaching endothelial as well as other perisinusoidal cells. The detached cells embolize downstream, causing further sinusoidal and possibly venular obstruction. Eventually, sinusoidal and centrilobular fibrosis ensues, causing hepatic congestion and manifesting clinically as portal hypertension. Later, the resulting low-flow state causes redistribution of the hepatic microcirculation and focal hepatic ischemia, culminating in centrilobular hepatocyte necrosis.

Budd-Chiari Syndrome

Postsinusoidal obstruction causes sinusoidal (and portal) pressure to increase. Increased sinusoidal pressure promotes centrilobular sinusoidal dilatation and congestion. The congested liver enlarges. Sinusoidal perfusion diminishes, and centrilobular ischemia and necrosis may occur. Stagnant blood flow and an underlying procoagulant state may precipitate concomitant thrombosis of the extrahepatic (10%) and intrahepatic (50%) portal veins. Areas in which there is simultaneous obstruction of the hepatic and portal veins undergo infarction. Perivenular fibrosis develops within weeks of the obstruction.

Sinusoidal Obstruction Syndrome

SOS usually manifests 1 to 2 weeks after stem cell transplantation. The first symptom is abdominal pain, followed by ascites, tender hepatomegaly, jaundice, and weight gain (from fluid retention). Laboratory abnormalities include direct hyperbilirubinemia initially with subsequent elevations in alkaline phosphatase and aminotransferases. Renal dysfunction (with up to 50% of patients requiring dialysis), diuretic-resistant fluid retention, recalcitrant thrombocytopenia resulting from splenic sequestration, and encephalopathy occur later. SOS is an acute or subacute illness that either fully resolves, usually in 2 to 3 weeks, or ends in death. All-cause fatality from SOS varies according to disease severity, with fatality rates in one series reported as 9%, 23%, and 98%, in mild, moderate, and severe disease, respectively. Patients who recover do not develop cirrhosis.

SOS is a clinical diagnosis that uses noninvasive criteria devised by groups from Seattle and Baltimore. Both sets of criteria use variable combinations of hyperbilirubinemia, weight gain, ascites, and hepatomegaly within 3 weeks of stem cell transplantation. The diagnosis can be confirmed by liver biopsy. If percutaneous biopsy is contraindicated because of thrombocytopenia, a transjugular approach may be employed, at which time the hepatic venous pressure gradient may also be measured. When elevated above 10 mm Hg, this gradient has a specificity of 90% in the appropriate clinical scenario.

Budd-Chiari Syndrome

The clinical manifestations and severity of BCS depend on the location and acuity of the venous obstruction. Asymptomatic disease occurs in patients with obstruction of only one hepatic vein or more than one hepatic vein with the development of collateral vessels. Slow obstruction of two hepatic veins results in chronic disease, whereas sudden obstruction of all three hepatic veins or the extrahepatic IVC may produce fulminant hepatic failure.

Patients classically present with ascites, hepatosplenomegaly, and right upper quadrant abdominal pain. Lower extremity edema and venous collaterals on the abdominal wall may be evident. The presentation is acute in 20% of patients. Serum values of aminotransferases, alkaline phosphatase, and bilirubin are moderately elevated, whereas those of plasma coagulation factors are diminished. Twenty-five percent of patients with acute BCS progress to fulminant hepatic failure. The presentation is chronic in 80% of patients; 20% of these patients progress to cirrhosis. Laboratory abnormalities are milder than in the acute form. The prognosis of chronic BCS has improved owing to advances in supportive care, with a current 1-year transplant-free survival of 80% and a 10-year transplant-free survival of 60%.

BCS is an imaging diagnosis. Liver biopsy may suggest the diagnosis but is not specific.