History and Physical Examination
Clinical risk factors for the development of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) include the following [17] :
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Younger age
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Positive hepatitis B/C serology
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Lower Karnofsky performance scale score
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Use of sirolimus, disease
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Myeloablative conditioning regimens, especially busulfan-based myeloablative conditioning regimens guided by pharmacokinetic monitoring
In addition, disease and disease status at transplant influence risk (eg, risk is low with acute lymphoblastic leukemia in first complete remission, high with refractory or relapsed non-Hodgkin lymphoma). [17] A Center for International Blood and Marrow Transplant Research (CIBMTR) risk calculator, which uses the above clinical risk factors, is available online.
Initial signs and symptoms of VOD/SOS include the following:
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Weight gain
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Increase in abdominal circumference
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Hepatomegaly
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Right upper quadrant pain
A bleeding tendency may be noted. Transfusion-refractory thrombocytopenia with no detectable cause is as an early and suggestive sign of VOD/SOS.
The onset of VOD/SOS usually occurs within the first 20 days after HSCT, with a peak 12 days posttransplantation. However, late-onset cases have been reported. In 2 pediatric studies, VOD/SOS occurred more than 20 days after HSCT (ranging from 21-509 d after HSCT) in 55% of patients in one study and 29% of patients in another study. [18, 19]
Clinical manifestations comprise part of the diagnostic criteria for VOD/SOS. Hyperbilirubinemia and imaging studies are also used for diagnosis. See DDx/Diagnostic Considerations and Workup.
Causes
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:
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Unrelated or HLA-mismatched donor
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Non–T-cell-depleted transplant
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Myeloablative-conditioning regimen
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Oral or high-dose busulfan-based regimen
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High-dose total-body irradiation (TBI)–based regimen
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Second HSCT
Patient- and disease-related factors include the following:
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Older age
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Karnofsky score below 90%
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Metabolic syndrome
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Female receiving norethindrone
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Advanced disease (beyond second complete remission [CR] or relapse/refractory)
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Thalassemia
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Genetic factors (GSTM1 polymorphism, C282Y allele, MTHFR 677CC/1298CC haplotype)
Factors related to the liver include the following [20] :
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Transaminase levels > 2.5 upper limit of normal (ULN)
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Serum bilirubin > 1.5 ULN
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Cirrhosis
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Active viral hepatitis
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Abdominal or hepatic irradiation
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Previous use of gemtuzumab ozogamicin (withdrawn from US market in June, 2010) or inotuzumab ozogamicin
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Hepatotoxic drugs
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Iron overload
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. [16, 1, 13] Whether the observed toxicity of busulfan is due to a hepatic first-pass effect following oral administration of busulfan is controversial. [21, 22, 23] However, a study comparing orally administered busulfan with intravenously administered busulfan showed a lower incidence of veno-occlusive disease associated with intravenously administered busulfan. [24]
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. [25]
Single-nucleotide polymorphisms of the donor may also be a factor in the onset of VOD/SOS in children receiving allogeneic HSCT. [26]
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.
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 |
