Practice Essentials
Along with graft versus host disease (GVHD) and cytomegalovirus (CMV) infection, hepatic veno-occlusive disease (VOD) is one of the most frequently encountered serious complications after hematopoietic stem cell transplantation (HSCT). The reported overall incidence rate of VOD ranges from 5% to more than 60% in children who have undergone HSCT, and similar rates have been reported in adults. [1, 2, 3, 4, 5, 6, 7]
The causes of VOD are still unclear, but a combination of pretransplant risk factors and transplant-related conditions are believed to trigger a primarily hepatic sinusoidal injury. This can quickly extend to a hepatocytic and panvasculitic disease, followed by multiorgan failure that is associated with substantial mortality. The initiating pathophysiological events have prompted the use of the term sinusoidal obstruction syndrome (SOS), which is often used together with the older descriptor (ie, VOD/SOS).
The risk of VOD/SOS in the pediatric population is not limited to a well-defined group of high-risk patients who have undergone transplantation. The disease frequently occurs outside this group. For example, patients treated for solid tumors (eg, Wilms tumor, neuroblastomas, and rhabdomyosarcomas [8, 9] ) are at risk for it. VOD/SOS has also been described in a patient with Burkitt lymphoma. [10]
Early identification of high-risk patients with severe disease is of the utmost importance because of the high mortality rates associated with severe cases. The onset of VOD/SOS usually occurs within the first 20 days after HSCT, with a peak 12 days posttransplantation. However, late-onset cases occur. Clinical and laboratory manifestations of VOD/SOS include the following:
-
Weight gain
-
Increase in abdominal circumference
-
Hepatomegaly
-
Right upper quadrant pain
-
Hyperbilirubinemia
-
Thrombocytopenia
Imaging studies can be valuable for assessing the liver. Reversal of flow in the portal and hepatic veins is the diagnostic finding on Doppler ultrasonography. See Presentation, DDx/Diagnostic Considerations, and Workup.
Defibrotide is approved for the treatment of adult and pediatric patients who have hepatic VOD/SOS with kidney or pulmonary dysfunction. Supportive care is also important. See Treatment and Medication.
Pathophysiology
The pathophysiology of sinusoidal obstructive syndrome remains obscure. The primary injury in veno-occlusive disease is most likely a lesion of the sinusoidal endothelial cells of hepatic venules. The first recognizable histologic changes are characterized by widening of the subendothelial zone, red cell extravasation, fibrin deposition, and expression of factor VIII/von Willebrand factor within venule walls, followed by necrosis of the perivenular hepatocytes. Late histological findings include deposits of extracellular matrix, an increased number of stellate cells, and subsequent sinusoidal fibrosis. This process eventually leads to complete venular obliteration, extensive hepatocellular necrosis, and widespread fibrous tissue replacement of normal liver.
The detritus, which consist of endothelial cells, Kupffer cells, and stellate cells, embolize and obstruct downstream sinusoidal flow, characteristically affecting the centrilobular zone 3. Zone 3 is nearest to the central hepatic venules, according to the distance from the afferent arterial supply. Therefore, it receives the least oxygen supply and is given the term centrilobular.
Occluded hepatic venules were not found during autopsy in 25% of patients with even severe veno-occlusive disease. Because involvement of the hepatic veins does not appear to be essential for the development of clinical signs of veno-occlusive disease, the term sinusoidal obstruction syndrome is increasingly used. [11, 12]
Numerous studies have demonstrated associations with various hemostatic derangements, such as antithrombin deficiency, protein C deficiency, ADAMTS 13 enzyme deficiency, and elevations of plasminogen activator inhibitor; however, no conclusive evidence of a thrombotic origin to the liver damage has been demonstrated. [13, 14]
Epidemiology
Frequency
Veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a rare but significant complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is associated with high posttransplantation morbidity and mortality rates. Precise estimates of frequency are difficult because the incidence varies depending on the preparative regimen, the type of transplantation, and the underlying disease. The reported overall incidence of VOD/SOS ranges from 5% to more than 60% in children, and similar rates have been reported in adults. [1, 2, 3, 4, 5, 6, 7]
A retrospective study by the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party suggested that VOD/SOS may be underdiagnosed as a major cause of multi-organ failure in patients receiving HSCT for acute leukemia. Review of EBMT registry data from 202 allogeneic HSCT patients reported to have died of multi-organ failure identified 70 patients (35%) for whom VOD/SOS could be considered a trigger for the multi-organ failure and of those, 48 (69%) were previously undiagnosed as having VOD/SOS. Most of the missed diagnoses were in late cases that developed beyond 21 days post-HSCT. [15]
VOD/SOS has no racial predilection, occurs equally in males and females, and occurs in both children and adults.
Mortality/Morbidity
Severe disease is associated with significant morbidity and a mortality rate of more than 90%. [16] In children, the mortality rate in patients with veno-occlusive disease 100 days posttransplantation is 38.5%, as opposed to 9% in patients who do not have veno-occlusive disease. [1]
Tables
Criteria |
Mild |
Moderate |
Severe |
Very Severe (Multi-Organ Dysfunction/Failure) |
Time since first clinical manifestations |
> 7 days |
5-7 days |
≤4 days |
Any time |
Bilirubin |
2 to < 3 mg/dL 34 to < 51 μmol/L |
3 to < 5 mg/dL 51 to < 85 μmol/L |
5 to < 8 mg/dL 85 to < 136 μmol/L or doubling of bilirubin within 48 hr |
≥8 mg/dL ≥136 μmol/L |
Transaminases |
≤2 x normal |
> 2 to 5 x normal |
> 5 to 8 x normal |
> 8 x normal |
Weight increase |
< 5% |
5% to < 10% |
5% to < 10% |
≥10% |
Kidney function |
< 1.2 x baseline |
1.2 to < 1.5 x baseline at transplant |
1.5 to < 2 x baseline at transplant |
≥2 x baseline at transplant or other signs of multi-organ dysfunction/failure |
