eMedicine Specialties > Pediatrics: General Medicine > Oncology

Veno-occlusive Hepatic Disease

Author: James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
Coauthor(s): Selim Corbacioglu, MD, Assistant Professor of Hematology-Oncology, Department of Pediatrics, University Children's Hospital, Ulm, Germany
Contributor Information and Disclosures

Updated: Jun 16, 2009

Introduction

Background

Along with graft versus host disease (GVHD) and cytomegalovirus (CMV) infection, veno-occlusive disease (VOD) is one of the most frequently encountered serious complications after stem cell transplantation. The reported overall incidence rate of veno-occlusive disease ranges from 5% to more than 60% in children who have undergone stem cell transplantation, and similar rates have been reported in adults.1,2,3,4,5,6,7

The causes of veno-occlusive disease are still unclear, but a combination of pretransplant risk factors and transplant-related conditions are believed to trigger a primarily hepatic sinusoidal injury. This can quickly extend to a hepatocytic and panvasculitic disease, which is followed by multiorgan failure that is associated with substantial mortality. The initiating pathophysiological events have prompted the suggestion that this form of liver disease be renamed sinusoidal obstruction syndrome (SOS).  

The risk of veno-occlusive disease in the pediatric population is not limited to a well-defined group of high-risk patients who have undergone transplantation. The disease frequently occurs outside this group. For example, patients treated for solid tumors (eg, neuroblastomas and rhabdomyosarcomas8 ) are at a high risk for developing veno-occlusive disease, especially after treatment with a combination of busulfan and melphalan. Busulfan-associated risk varies with the administration strategy used and does not appear to be reduced when given in a pharmacokinetically controlled dosing strategy.9,10,11,12

Pathophysiology

The pathophysiology of veno-occlusive disease remains obscure. The primary injury in veno-occlusive disease is most likely a lesion of the sinusoidal endothelial cells of hepatic venules. The first recognizable histologic changes are characterized by widening of the subendothelial zone, red cell extravasation, fibrin deposition, and expression of factor VIII/von Willebrand factor within venule walls, followed by necrosis of the perivenular hepatocytes. Late histological findings include deposits of extracellular matrix, an increased number of stellate cells, and subsequent sinusoidal fibrosis. This process eventually leads to complete venular obliteration, extensive hepatocellular necrosis, and widespread fibrous tissue replacement of normal liver.

The detritus, which consist of endothelial cells, Kupffer cells, and stellate cells, embolize and obstruct downstream sinusoidal flow, characteristically affecting the centrilobular zone 3. Zone 3 is nearest to the central hepatic venules, according to the distance from the afferent arterial supply. Therefore, it receives the least oxygen supply and is given the term centrilobular.

Occluded hepatic venules were not found during autopsy in 25% of patients with even severe veno-occlusive disease. Because involvement of the hepatic veins does not appear to be essential for the development of clinical signs of veno-occlusive disease, a proposal has been made to change the name of the disease to sinusoidal obstruction syndrome.13,14

Numerous studies have demonstrated associations with various hemostatic derangements, such as antithrombin deficiency, protein C deficiency, ADAMTS 13 enzyme deficiency, and elevations of plasminogen activator inhibitor; however, no conclusive evidence of a thrombotic origin to the liver damage has been demonstrated.15,16

Frequency

United States

Veno-occlusive disease is a rare but significant complication of allogeneic bone marrow transplantation (BMT). Along with GVHD and CMV infection, veno-occlusive disease is one of the most common serious complications after stem cell transplantation and is associated with high posttransplantation morbidity and mortality rates. Precise estimates of frequency are difficult because the incidence of veno-occlusive disease varies depending on the preparative regimen, the type of transplantation, and the underlying disease. The reported overall incidence of veno-occlusive disease ranges from 5% to more than 60% in children, and similar rates have been reported in adults.1,2,3,4,5,6,7

International

The worldwide incidence rate of veno-occlusive disease appears to be similar to that in the United States.

Mortality/Morbidity

Severe disease is associated with significant morbidity and a mortality rate of more than 90%.17 In children, the mortality rate in patients with veno-occlusive disease 100 days posttransplantation is 38.5%, as opposed to 9% in patients who do not have veno-occlusive disease.1

Early identification of high-risk patients with severe disease is of the utmost importance because of the high mortality rates associated with severe veno-occlusive disease.

The severity of veno-occlusive disease is divided into the following 3 categories:

  • Mild disease
    • No adverse effects from veno-occlusive disease
    • No treatment necessary
    • Self-limiting
  • Moderate disease
    • No adverse effects from veno-occlusive disease
    • Requires treatment (pain medication, diuretics, other supportive care)
  • Severe disease
    • Unresolved signs and symptoms of veno-occlusive disease 100 days after stem cell transplantation
    • Death due to complications directly attributable to veno-occlusive disease

Severe veno-occlusive disease was more precisely defined based on the presence of multiorgan failure in addition to veno-occlusive disease. Multiorgan failure is characterized by oxygen requirement (with an oxygen saturation of <90% on room air, ventilator dependence, or both), renal dysfunction (defined as doubling of baseline creatinine levels, dialysis dependence, or both), and/or encephalopathy.18

Race

Veno-occlusive disease has no racial predilection.

Sex

Veno-occlusive disease occurs equally in males and females.

Age

Veno-occlusive disease occurs in both children and adults.

Clinical

History

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, Wyeth)  
  • Allogeneic HSCT for leukemia beyond the second relapse  
  • Conditioning with busulfan, melphalan, or both  
  • Osteopetrosis
  • Macrophage-activating syndromes (eg, hemophagocytic lymphohistiocytosis, Griscelli syndrome)

Physical

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.19,20

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.17,6 These criteria predict veno-occlusive disease with an accuracy of more than 90% but have a relatively low sensitivity of 56%.21

  • 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)
    • Ascites
    • Weight gain of more than 5% above the reference range

Causes

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.17,1,15 Whether the observed toxicity of busulfan is due to a hepatic first-pass effect following oral administration of busulfan is controversial.9,10,22  However, a study comparing orally administered busulfan with intravenously administered busulfan showed decreased incidence of veno-occlusive disease associated with intravenously administered busulfan.23

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.

More on Veno-occlusive Hepatic Disease

Overview: Veno-occlusive Hepatic Disease
Differential Diagnoses & Workup: Veno-occlusive Hepatic Disease
Treatment & Medication: Veno-occlusive Hepatic Disease
Follow-up: Veno-occlusive Hepatic Disease
References
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References

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Further Reading

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Keywords

veno-occlusive hepatic disease, veno-occlusive disease, VOD, bone marrow transplant, BMT, bone marrow transplantation, graft versus host disease, GVHD, stem cell transplantation, cytomegalovirus, CMV, sinusoidal obstruction syndrome, SOS, transfusion-refractory thrombocytopenia, ascites, hepatomegaly, complete venular obliteration, hepatocellular necrosis, osteopetrosis, busulfan, melphalan, hyperbilirubinemia, neuroblastoma, liver transplantation, treatment, diagnosis

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Contributor Information and Disclosures

Author

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

Coauthor(s)

Selim Corbacioglu, MD, Assistant Professor of Hematology-Oncology, Department of Pediatrics, University Children's Hospital, Ulm, Germany
Selim Corbacioglu, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, European Group for Blood and Marrow Transplantation, and European Hematology Association
Disclosure: Nothing to disclose.

Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
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