The most common setting for hepatic veno-occlusive disease (VOD) in the United States is following high-dose chemotherapy in hematopoietic stem cell transplantation. VOD is not commonly recognized as a complication of standard dose chemotherapy. An additional uncommon iatrogenic cause of VOD is long-term immunosuppression with azathioprine in renal and liver transplant patients. Hepatitis C confers a significant risk for VOD and may be one of the predisposing factors in transplant patients. VOD may also be caused by plant-derived pyrrolizidine alkaloids. Sporadic cases may be due to use of herbal teas, whereas individuals from developing countries may sustain VOD in epidemics in which plant alkaloids contaminate grain fields.

The hallmark features of VOD are hyperbilirubinemia, painful hepatomegaly, and fluid retention. In pyrrolizidine alkaloid-induced disease the course of the disease is variable and symptoms may persist for years, whereas VOD in hematopoietic stem cell transplantation has a more rapid course. Further remarks will address VOD due to hematopoietic stem cell transplantation. Diagnosis can usually be made based on clinical criteria. Commonly used clinical criteria for the diagnosis are: bilirubin > 2 mg/dl, hepatomegaly or RUQ pain of liver origin and >2% weight gain due to fluid accumulation; the diagnosis requires 2 of 3 criteria, occurring within 20 days of transplantation. The diagnosis can only be made when hyperacute graft-versus-host disease, sepsis, cardiac failure, and tumor infiltration have been ruled out. These criteria were developed for regimens that contain cyclophosphamide but may not apply to regimens without cyclophosphamide, which may have a later onset of disease. Ultrasound can exclude tumor infiltration and biliary tract disease and can confirm hepatomegaly and ascites, but ultrasound is not particularly helpful in establishing the diagnosis. Transvenous liver biopsy may be done in patients with thrombocytopenia post-transplantation and the most common indication would be to differentiate VOD from acute graft-versus-host disease.

The incidence of VOD varies from 1 to 50% between hematopoietic stem cell transplantation units. The risk of VOD is largely dependent on patient selection criteria and choice of chemotherapy used. The risk is highest when transplantation is done for malignancy, since the doses of chemotherapy are higher. Hematopoietic stem cell transplantation units that have broader eligibility criteria and that use high-dose chemotherapy and higher doses of total body irradiation will gain efficacy against malignancies and be able to treat a sicker population, but at the cost of more deaths from VOD. Careful selection of patients with low tumor burden, ongoing response to standard-dose chemotherapy and good performance status, and use of less toxic conditioning regimens will result in a lower incidence of VOD. Other major risk factors are coexistent hepatitis C, bilirubin > 4 mg/dl within 10 days of transplantation, and ongoing infections at the time of chemotherapy.

Published graphs can be used to predict the severity of VOD. Mortality of mild, moderate, and severe VOD is 3, 20, and 98%, respectively. Death usually occurs between 30 and 60 days after the chemotherapy has been given and is due to liver failure that is often accompanied by multiorgan failure. In patients with severe VOD (based on the published graphs) without hepatorenal syndrome or cardiopulmonary failure, therapy with recombinant tissue plasminogen activator (tPA) plus heparin is warranted. However improvement occurs in less than 30%. There is currently no other prophylactic or therapeutic strategy that has proven benefit.