A. Clinical Syndrome [1,2]

1. Hepatomegaly (usually with abdominal pain)
2. Fluid Retention
   1. Weight gain >5% of baseline usually due to formation of ascites
   2. Hepatorenal syndrome pathophysiology is also usually present
3. Hyperbilirubinemia - total bilirubin >15mg/dL

B. Etiology / Clinical Setting

1. Endothelial damage
   1. Deposition of Factor VIII and Fibrinogen in Subendothelial Zones
   2. Occurs primarily in venules; platelet function is thought to be normal in VOD
   3. Possible relation to HUS / TTP syndromes (but platelet function is abnormal in these)
2. Hepatocyte Injury with Necrosis
   1. Occurs due to obstruction of venous flow in liver
   2. This obstruction is due to clots in only small venules (not larger vessels)
   3. Fibrin clots form on damaged endothelial cells and lead to ischemic hepatocyte damage
   4. Tumor necrosis factor alpha (TNFa) is produced in large quantities
3. Bone Marrow Transplant Setting [2]
   1. VOD occurs in <5% of autologous transplants
   2. VOD occurs in ~50% of allogeneic transplants, depending on defining criteria
   3. Fatal in 98% of patients with severe VOD
   4. Seen during conditioning regimen as well as after transplant infusion
   5. Cyclophosphamide, busulfan are particularly associated with VOD
4. Patients at High Risk
   1. Pre-transplant liver disease
   2. Allogeneic transplants - especially receiving methotrexate for GVHD prophylaxis
   3. Very high dose pre-transplant and other chemotherapeutic regimens
   4. Immunosuppressive regimens including cyclosporin and OKT3 and methotrexate
   5. Irradiation to the liver also causes VOD
5. Must distinguish from Graft versus Host disease (GVHD)
6. In VOD, there is considerable fluid retention (not seen in GVHD)
7. Possible now to predict VOD based on body weight and total bilirubin pre-transplant
8. Liver biopsy is dangerous and insensitive for making diagnosis

C. Complications

1. Renal Failure (? Hepatorenal syndrome)
2. Multiorgan system failure
3. Bleeding due to poor synthetic function
4. Encephalopathy

D. Treatment

1. Heparin
   1. Given for 10 days, continuous infusion
   2. Initially 1000U bolus followed by 150U/kg/d x 10 days
   3. Bleeding risk is very high
2. Tissue Plasminogen Activator (TPA)
   1. 10mg/d x 2 days
   2. Recent data indicate response within 4 days of beginning TPA
   3. Bleeding is often seen
3. Ursodiol (Actigal®) [3]
   1. Bile acid (ursodeoxycholic acid) given to patients undergoing Allogeneic BMT for CML
   2. All patients received induction (preparative) therapy with busulfan + cyclophosphamide
   3. Ursodiol (300mg bid) versus placebo was given peritransplant
   4. Ursodiol reduces progression to cirrhosis and failure in various liver diseases
   5. In BMT, hepatic VOD reduced from 40% to 15% with ursodiol treatment [4]
   6. Hematologic risk of relapse in this CML cohort was similar with ursodiol versus placebo
4. Defibrotide - DNA extract from lung may reduce risk or treat VOD
5. Prostaglandin E1 - may have some prophylactic benefits

References

1. Miller KB and Graeme-Cook FM. 1996. NEJM. 334(25):1655 (Case Report)
2. Copelan EA. 2006. NEJM. 354(17):1813
3. Kowdley KV. 2000. Am J Med. 108(6):481
4. Essell JH, Schroeder MT, Harman GS, et al. 1998. Ann Intern Med. 128(12):975