Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies

Table 1 Risk factors of hepatic veno-occlusive disease

Risk factors	Ref.
Patient factors
Younger age in children	[75-77]
Older age in adults	[78]
Poor performance status	[13,79,80]
Glutathione S-transferase M1 null genotype	[81]
Hemochromatosis C282Y allele	[82]
Pre-existing hepatic dysfunction	[2-4,79]
Hypoalbuminemia	[83]
Hyperbilirubinemia	[83]
High serum ferritin	[84]
Positive CMV serology	[85]
Elevated plasma transforming growth factor β level	[86]
Hepatitis B or C infection	[7,87-90]
History of pancreatitis	[85]
Disease factors
Thalassemia major	[76]
Advanced malignancy	[83,91]
Acute leukemia	[89]
Neuroblastoma	[75,77]
Delayed platelet engraftment	[75,76]
Presence of acute graft-vs-host disease	[83]
Treatment factors
Interval between diagnosis and transplantation greater than 13 mo	[83]
Allogeneic HSCT	[75,79]
Unrelated donor HSCT	[3,13,85,91]
Mismatched donor	[3,83]
Second or subsequent transplants	[7,84]
Prior use of gemtuzumab ozogamicin	[92]
Prior use of norethisterone	[93]
Prior abdominal irradiation	[3,7,77,79]
Use of total parenteral nutrition within 30 d before HSCT	[85]
High dose cytoreductive therapy	[79]
Conditioning regimen containing busulfan with or without cyclophosphamide	[3,75,76,84,85]
Conditioning regimen containing fludarabine	[85]
Conditioning regimen containing melphalan	[94,95]
Total body irradiation	[83,84]
Graft-vs-host disease prophylaxis with cyclosporin with or without methotrexate	[80,83,85]
Use of sirolimus	[96]
Use of tranexamic acid	[97]
Platelet transfusion containing ABO-incompatible plasma	[95]

HSCT: Hematopoietic stem cell transplantation.

Table 2 Randomized controlled trials of ursodeoxycholic acid for hepatic veno-occlusive disease

Trial reference	Essell et al[26] 1998	Ohashi et al[27] 2000	Ruutu et al[28] 2002	Park et al[29] 2002
Blinding	Double-blind	Non-blind	Non-blind	Non-blind
Type of transplants	Allogeneic	Allogeneic or autologous	Allogeneic	Allogeneic or autologous
Donor	Related	Variable	Variable	NA
Stem cell source	Bone marrow	NA	Variable	NA
Conditioning	Busulfan and cyclophosphamide or busulfan alone	Variable	Variable	Variable
No. of patients (treatment vs control)	35 vs 32	71 vs 65	124 vs 120	82 vs 83
Treatment regimen	Ursodeoxycholic acid 300 mg BD (< 90 kg) or 300/600 mg BD (> 90 kg), given before conditioning till Day+80	Ursodeoxycholic acid 600 mg daily, given from Day-21 till Day+80	Ursodeoxycholic acid 6 mg/kg per day BD, given 1 d before conditioning till Day+90	Ursodeoxycholic acid 300 mg BD, heparin 5 units/kg per hour, given 12-24 h before conditioning till Day+30
Control	Placebo	No drug	No drug	Heparin alone
Age of patients (yr, treatment vs control)	Mean 38 (22-56) vs 37 (21-56)	Mean 34.5 vs 35.7	Median 38 (5-59) vs 40 (1-58)	Median 39 vs 38
VOD criteria	Seattle	Seattle	Baltimore, Seattle	Modified Seattle
Frequency of VOD (treatment vs control)	14.3% vs 40.6%	2.8% vs 18.5%	Baltimore 2.4% vs 4.2%; Seattle 11.3% vs 11.7%	15.9% vs 19.3%
Mortality at Day+100 (treatment vs control)	22.9% vs 40.6%	NA	NA	11.0% vs 10.8%

NA: Data not available; VOD: Veno-occlusive disease.