Veno-occlusive Hepatic Disease Clinical Presentation
- Author: James L Harper, MD; Chief Editor: Jennifer Reikes Willert, MD more...
In children, the following criteria are associated with a significantly increased risk for developing veno-occlusive disease (VOD) and should be identified prior to bone marrow transplantation (BMT):
Preexisting liver disease (eg, liver fibrosis, hepatitis, abdominal irradiation, pretransplantation transaminitis of unclear origin)
Second myeloablative hematopoietic stem cell transplantation (HSCT)
History of treatment with gemtuzumab ozogamicin (Mylotarg, Pfizer); withdrawn from US market June, 2010
Allogeneic HSCT for leukemia beyond the second relapse
Conditioning with busulfan, melphalan, or both
Macrophage-activating syndromes (eg, hemophagocytic lymphohistiocytosis, Griscelli syndrome)
The clinical symptoms of veno-occlusive disease include weight gain, an increase in abdominal circumference, hepatomegaly, right upper quadrant pain, ascites, and elevated total and direct bilirubin levels. The onset of transfusion-refractory thrombocytopenia with no detectable cause is frequently noted as an early and suggestive sign.
The onset of veno-occlusive disease usually occurs prior to 20 days after HSCT, with a peak 12 days posttransplantation. However, the onset of veno-occlusive disease has been reported even later. In 2 recent pediatric studies, veno-occlusive disease occurred more than 20 days after HSCT (ranging from 21-509 d after HSCT) in 55% of patients and 29% of patients, respectively.[18, 19]
Typical early symptoms include weight gain and tender hepatomegaly, followed by edema and ascites, which are reflected in the clinical criteria developed by the Seattle and Baltimore groups.[16, 6] These criteria predict veno-occlusive disease with an accuracy of more than 90% but have a relatively low sensitivity of 56%.
According to the modified Seattle criteria, 2 or more of the following must be present prior to 20 days after stem cell transplantation for a diagnosis of veno-occlusive disease:
- Bilirubin level of more than 2 mg/dL (34 µmol/L)
- Hepatomegaly and upper right quadrant pain of liver origin
- Ascites and/or unexplained weight gain of more than 2% above the reference range
According to the Baltimore criteria, hyperbilirubinemia (≥2 mg/dL) and 2 or more of the following must be present prior to 21 days after stem cell transplantation:
- Hepatomegaly (usually painful)
- Weight gain of more than 5% above the reference range
The principal cause of most cases of veno-occlusive disease is the toxicity of the preparative regimen for BMT. Several clinical publications have confirmed that administration of busulfan-containing preparative regimens is a significant risk factor for veno-occlusive disease.[16, 1, 14] 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 decreased incidence of veno-occlusive disease associated with intravenously administered busulfan.
Nagler et al performed a study on 257 acute myeloid leukemia adult hematopoietic stem cell transplant (HSCT) recipients to assess the incidence of hepatic sinusoidal obstructive syndrome (SOS) when busulfan is administered intravenously (i.v. BU). The authors found that the factors associated with the occurrence of SOS were human leukocyte antigen(HLA) mismatched donor HSCT and patients transplanted in non-remission. The authors concluded that the outcomes of HSCT using i.v. BU are encouraging since SOS incidence is low and it is influenced by the type of donor and disease status at the time of transplant.
In patients who have not undergone transplantation, veno-occlusive disease has occurred after radiation to the liver and after therapy with actinomycin D, which is a known hepatotoxic agent.
Veno-occlusive disease 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.
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