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    Drugs & Diseases > Pediatrics: General Medicine

    Veno-occlusive Hepatic Disease

    Updated: Mar 31, 2016
    • Author: James L Harper, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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    Overview

    Background

    Along with graft versus host disease (GVHD) and cytomegalovirus (CMV) infection, veno-occlusive disease (VOD) or Sinusoidal Obstruction Syndrome (SOS), 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 this form of liver disease be renamed sinusoidal obstruction syndrome (SOS).

    The risk of sinusoidal obstruction syndrome 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, Wilms tumor, neuroblastomas, and rhabdomyosarcomas [8, 9] ) are at risk for developing veno-occlusive disease. SOS has also been described in a patient with Burkitt lymphoma. [10]

    Single nucleotide polymorphisms of the donor may also be a factor in the onset of SOS in children receiving an allogeneic transplant. [11]

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    Pathophysiology

    The pathophysiology of sinusoidal obstructive syndrome 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. [12, 13]

    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. [14, 15]

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    Epidemiology

    Frequency

    United States

    Sinusoidal obstructive syndrome is a rare but significant complication of allogeneic bone marrow transplantation (BMT). Along with GVHD and CMV infection, sinusoidal obstructive syndrome 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 sinusoidal obstructive syndrome 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%. [16] 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 sinusoidal obstructive syndromeis divided into the following 3 categories:

    • Mild disease

      • No adverse effects from sinusoidal obstructive syndrome

      • No treatment necessary

      • Self-limiting

    • Moderate disease

      • No adverse effects from sinusoidal obstructive syndrome

      • Requires treatment (pain medication, diuretics, other supportive care)

    • Severe disease

      • Unresolved signs and symptoms of sinusoidal obstructive syndrome 100 days after stem cell transplantation

      • Death due to complications directly attributable to sinusoidal obstructive syndrome

    Severe sinusoidal obstructive syndrome can be 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. [17]

    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.

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