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Summer 1996Volume 3, Number 1 |
Hepatic veno-occlusive disease (VOD) represents one of the most serious therapy-related complications associated with bone marrow transplantation. VOD occurs in 20-60% of bone marrow recipients. Variability in the reported incidence is due to a number of factors including the intensity and type of preparative regimen, pretransplant patient characteristics, and diagnostic sensitivity. Because the clinical scenario, particularly severe thrombocytopenia, often precludes liver biopsy, the diagnosis is usually established by clinical criteria. The clinical picture includes hepatomegaly (often with hepatic pain), weight gain due to edema and ascites, and hyperbilirubinemia.1 The onset of symptoms often occurs within days of the initiation of the preparative chemoradiation regimen and usually by 20-30 days posttransplant, depending on the diagnostic criteria.2,3 This complex of signs and symptoms must be distinguished from other posttransplant causes of liver disease acute graft-versus-host disease, fungal infiltration, bacterial sepsis, drug toxicity or TPN-associated hepatitis, and passive congestion of the liver. Diagnosis of other causes of hyperbilirubinemia can often be established by clinical signs or diagnostic tests. Nevertheless, hepatic disease in a subset of patients lacking clear-cut features of VOD is often classified as liver dysfunction of uncertain etiology.
The majority of patients with VOD undergo spontaneous resolution by one month posttransplant, without increased morbidity. Patients with severe VOD may develop marked hyperbilirubinemia, hepatic encephalopathy, and hemorrhage due to coagulation deficiencies. Death usually follows development of the hepatorenal syndrome and associated cardiopulmonary failure.
Factors Associated with the Development of VOD
The risk of developing posttransplant VOD appears to be related to several pretransplant characteristics including elevated transaminases at the time of initiation of the preparative regimen. Whether a prior, resolved hepatitis is associated with an increased risk of VOD is unclear. Extensive prior chemotherapy, especially in the setting of a second bone marrow transplant, is associated with an increased incidence of VOD. Some studies suggest that older patients have an increased frequency of VOD, but other studies fail to confirm this finding.2-4 Infection at the time the preparative regimen is administered is associated with an increased incidence of VOD, suggesting that cytokines may be associated with the initiation of the process.5
Clearly, the preparative regimen is an important factor in the development of VOD. Intensive preparative regimens, particularly those with increased doses of radiation therapy, have been associated with an increased likelihood of VOD. The relationship between high-dose busulfan and the development of VOD is still unclear; an increased incidence of VOD has been noted in busulfan-treated patients in some studies, but not others.2,3,5-7 The use of methotrexate posttransplant for GVHD prophylaxis in busulfan-prepared patients is associated with an increased incidence of VOD.8 Although one would expect a lower incidence of VOD in recipients of autologous transplants than in allogeneic transplant recipients, this expectation has not been substantiated, and the risk may relate more to the intensity of the preparative regimen than to the nature of the transplanted marrow. Whether or not an increased incidence occurs in recipients of matched unrelated donor transplants has not been established.
The histopathology of hepatic VOD reveals variable disruption of blood flow in the terminal hepatic venules, ultimately resulting in damage to the zone 3 hepatocytes.9 The process initially presents with subendothelial edema resulting in concentric narrowing of the terminal and central veins, often progressing to collagen deposition with sclerosis of the venules. The deposition of factor VIII and fibrinogen has been noted. Secondary damage to zone 3 hepatocytes presumably results from congested sinusoids and increased venous pressure. While an elevated mean hepatic artery pressure reflecting intrahepatic hypertension has been reported in patients with VOD, Doppler ultrasound is often diagnostic only in the setting of advanced disease.10 With clinical resolution of VOD, recanalization occurs. When clinically feasible, transcutaneous liver biopsies may help to establish the diagnosis. Coagulopathies often preclude biopsy, however. Transjugular biopsies may be helpful, although the specimens are often very small. Autopsy material has revealed some of these histological findings in patients in whom the diagnosis of VOD was not clinically established, suggesting that the pathophysiological process noted in VOD can occur subclinically.
Other laboratory abnormalities in patients with VOD include increased levels of endothelial cell markers such as vWF and procollagen peptides, both of which may reflect the ongoing pathological process.11,12 Coagulation abnormalities include decreased levels of antithrombin 3 and protein C, as well as resistance to platelet transfusions, reflecting the localized hypercoagulable state associated with VOD.13 Decreased levels of factor VII and protein S have also been noted. Elevation of cytokines such as tumor necrosis factor alpha and interleukin-1 beta may reflect either an initiating factor or an inflammatory response to VOD.14 These findings do not result in a unifying etiology of VOD. Furthermore, the reliability of these findings in establishing a diagnosis is uncertain, since some of these abnormalities have been noted in transplant patients who did not develop VOD.
The majority of patients survive VOD. The condition resolves spontaneously, often requiring only careful fluid management. Nevertheless, approximately 25% of patients develop life-threatening disease. A model has been developed using rate of increase in weight and bilirubin level to predict eventual development of severe disease.15 This model is highly specific, but only moderately sensitive. Both the severity of VOD and the likelihood of survival are associated with the peak level of bilirubin.
Attempts have been made to prevent severe VOD. Clearly, exclusion of high-risk individuals from transplantation or limitation of the intensity of the preparative regimen would decrease both incidence and severity, but these strategies would also limit the wider application and possibly the success rate of marrow grafting. Another strategy is to defer transplantation, if possible, until hepatitis or infection resolves. Early studies with the methylxanthine analog pentoxifylline (Trental®) which decreases TNF-alpha production suggested a decreased incidence of VOD. However, subsequent studies have had mixed results, and for the most part the use of pentoxifylline for this indication has been abandoned.16,17 Limited experience in a randomized study with prophylactic ursodeoxycholic acid also suggested a decrease in the incidence of VOD.18 Prostaglandin E1 prophylaxis has been attempted, but was associated with significant side-effects and little efficacy.19
Several investigators have used low-dose heparin by continuous infusion beginning with the administration of the preparative regimen and continuing for 14 to 30 days posttransplant in an effort to prevent VOD.20-23 In most series, use of low-dose heparin, despite concurrent severe thrombocytopenia, has not resulted in an increased incidence of hemorrhage. One randomized study reported a decrease in the incidence of VOD, but another reported no effect. Despite the lack of proven efficacy, heparin prophylaxis is used in many centers in high-risk patients. In our experience, the overall incidence of VOD seems unchanged, but severe VOD seems less common in patients receiving heparin prophylaxis.
Treatment of established VOD remains problematic. The primary mode of therapy is supportive, consisting of careful fluid and electrolyte management. Diuretics may be required if clinical manifestations of fluid overload are present. Given the role hepatorenal syndrome plays in the development of fluid overload in this condition, spironolactone is usually the drug of choice. Fluid management is difficult because intravascular volume is often decreased, despite the excess of extravascular fluid. The concurrent use of other drugs affecting renal function (ie, cyclosporine and amphotericin) further complicates the clinical picture. Dialysis and mechanical ventilation have been utilized, but in this setting the outcome for patients requiring these interventions is extremely poor. No evidence supports the use of corticosteroids, heparin, or pentoxifylline in the treatment of established VOD. A small group of patients with VOD has been treated with PGE1, but evidence of efficacy is limited.19,24 A few patients have been treated surgically with liver transplantation, and, although technically successful, the procedure has not improved the long-term outcome.25
| No evidence supports the use of corticosteroids, heparin, or pentoxifylline in the treatment of established VOD. A small group of patients with VOD has been treated with PGE1, but evidence of efficacy is limited. |
Several investigators have used recombinant human t-PA (rt-PA), usually accompanied by heparin therapy, in the treatment of severe VOD.26-29 Approximately half the patients have had rapid responses, some of which have been sustained. However, a number of hemorrhagic catastrophes have also occurred, and therefore, rt-PA therapy must be approached with great caution. Thus, at present, no definitive therapy exists for the treatment of life-threatening VOD.
Joel Rappeport, MD
Department of Medicine
Yale University School of Medicine
New Haven, Connecticut
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