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 pathophysiologic 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 also 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 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 histologic 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 replacement of normal liver with fibrous tissue.
The detritus, which consists of endothelial cells, Kupffer cells, and stellate cells, embolizes and obstructs 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]
Etiology
Risk factors for veno-occlusive disease include those related to the transplant, those related to the patient and disease, and those related to the liver.
Transplant-related factors include the following:
-
Unrelated or HLA-mismatched donor
-
Non–T-cell-depleted transplant
-
Myeloablative-conditioning regimen
-
Oral or high-dose busulfan-based regimen
-
High-dose total-body irradiation (TBI)–based regimen
-
Second HSCT
Patient- and disease-related factors include the following:
-
Older age
-
Karnofsky score below 90%
-
Metabolic syndrome
-
Female receiving norethindrone
-
Advanced disease (beyond second complete remission [CR] or relapse/refractory)
-
Thalassemia
-
Genetic factors (GSTM1 polymorphism, C282Y allele, MTHFR 677CC/1298CC haplotype)
Factors related to the liver include the following [15] :
-
Transaminase levels > 2.5 upper limit of normal (ULN)
-
Serum bilirubin > 1.5 ULN
-
Cirrhosis
-
Active viral hepatitis
-
Abdominal or hepatic irradiation
-
Previous use of gemtuzumab ozogamicin (withdrawn from US market in 2010) or inotuzumab ozogamicin
-
Hepatotoxic drugs
-
Iron overload
A retrospective study of 2886 allogeneic transplantations from 71 centers reported a correlation between the number of risk factors and the development of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). Although the over all incidence was low (2.4%), patients with VOD/SOS all had between one and eight risk factors and 48% of these patients had 4 or more risk factors. [16]
The principal cause of most cases of veno-occlusive disease is the toxicity of the preparative regimen for HSCT. Several clinical publications have confirmed that administration of busulfan-containing preparative regimens is a significant risk factor for veno-occlusive disease. [17, 1, 13] Whether the observed toxicity of busulfan is due to a hepatic first-pass effect following oral administration of busulfan is controversial. [18, 19, 20] However, a study comparing orally administered busulfan with intravenously administered busulfan showed a lower incidence of veno-occlusive disease associated with intravenously administered busulfan. [21]
In a study by Nagler et al of 257 adult acute myeloid leukemia patients whose conditioning regimen for HSCT included intravenous busulfan, the factors associated with the occurrence of SOS were human leukocyte antigen (HLA)-mismatched donor HSCT and transplantation during non-remission. The authors concluded that the outcomes of HSCT using intravenous busulfan are encouraging since SOS incidence is low and it is influenced by the type of donor and disease status at the time of transplant. [22]
Single-nucleotide polymorphisms of the donor may also be a factor in the onset of VOD/SOS in children receiving allogeneic HSCT. [23]
In patients who have not undergone HSCT, VOD/SOS has occurred after radiation to the liver and after therapy with actinomycin D, which is a known hepatotoxic agent. VOD/SOS in the liver has occurred following liver transplantation.
The end result of inflammation due to the preparative regimen or other causes of vasculitis is a narrowed lumen of the hepatic sinusoids, the venules, and, eventually, the veins. The first result is bidirectional flow, followed by reversal of flow in the veins observed using Doppler ultrasonography. Obstruction of the hepatic and portal outflow causes engorgement of the liver and centrilobular necrosis in centrilobular zone 3. This also results in increased levels of bilirubin, γ-glutamyltransferase (GGT), and alkaline phosphatase.
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. [24]
VOD/SOS has no racial predilection, occurs equally in males and females, and occurs in both children and adults.
Prognosis
Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is associated with significant morbidity and a mortality rate of more than 90%. [17] 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] Some degree of liver dysfunction is observed in all cases of post-HSCT hepatic VOD/SOS; however, in rare severe cases, overt liver failure may be observed.
Kidney failure may be secondary to hepatorenal syndrome, as well as direct injury by the vasculopathy. In patients who have undergone transplantation, numerous frequently used nephrotoxic drugs (eg, vancomycin, amphotericin B, cyclosporine) can result in preexisting kidney dysfunction and loss of kidney function reserve. Separating the effects of those drugs from the effects of VOD/SOS may be difficult.
Other commonly observed complications include the following:
-
Pulmonary failure
-
Neurologic compromise
-
Increased risk of infectious complications due to peritoneal drainage and transfer of an immunodeficient patient to intensive care units with no laminar air flow
-
Severe consumptive coagulopathy with an increased risk for thrombosis and bleeding
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% |
≥10% |
Kidney function |
baseline at transplant |
< 1.5 x baseline at transplant |
1.5 to < 2 x baseline at transplant |
≥2 x baseline at transplant or diagnosis of multi-organ dysfunction/failure |
