Hepatic veno-occlusive disease (VOD)

Also known as sinusoidal obstruction syndrome.

Affects the sinusoidal endothelial cells of the liver.

A non-hematological toxicity associated with bone marrow transplant.

Clinical syndrome characterized by jaundice, painful hepatomegaly and/or fluid retention; ascites and encephalopathy are late manifestations.

A complication of stem cell transplant and cytotoxic therapy.

Most cases result from cytotoxic chemotherapy or high-dose radiation, especially in patients receiving a hematopoietic stem cell transplant.

Damage to endothelal cells implicated.

Primarily involves injury to hepatic sinusoidal endothelial cells, with responses including vein microthrombosis, , fibrin deposition, ischemia and fibrogenesis.

Veno-occlusive disease is due to acute injury and loss of intrasinoisal endothelial cells that result in obstruction of sinusoidal bloodflow and liver injuries: drugs as usual cause-the most common myeloablative agents used in preparation for hemetppoetic cell transplantion.

The endothelium is normally smooth and a selective permeable vascular barrier.

Potentially life-threatening they contribute significantly treatment-related toxicity, moribidity and mortality.

Incidence varies widely but approaches 13% of patients who undergo bone marrow transplants with myeloproliferative conditioning.

Variation in the incidence reflects different conditioning regimen, there are intensity, type of transplant and is likely to be undereported.

Histological findings include fibrous occlusion of terminal hepatic venous lumens, fibrosis of hepatic sinusoids and necrosis of zone 3 hepatocytes.

Develops in 10-15% of patients undergoing allogeneic bone marrow transplantation, and as high is 60% in high-risk patients.

Typically occurs within the first 21 days following hematopoetic stem cell transplantion.

Life-threatening in 30-50% of cases in high-risk settings.

In severe VOD multiorgan failure or dysfunction may be associated with a greater than 80% mortality.

The endothelial surface is usually smooth and has a selectively permeable vascular barrier.

The endothelial barrier integrity is established by a balance between contractile forces within endothelial cells creating intercellular gaps and the adhesive forces between endothelial cells restricting such gaps.

With injury endothelial cells swell, become activated and more adhesive.

Endothelial cells become rounded, and create gaps allowing fluid and blood cells to exit the vasculature and into the space of Disse.

With injury fibrin and cellular debris can combine within the hepatic sinusoids leading to congestion of hepatic sinusoids.

Congestion of hepatic sinusoids can cause liver swelling, pain and ultimately progress to reversal of portal flow, portal hypertension and hepato- renal syndrome, multi organ failure and death.

Initiating event appears to be injury to hepatic sinusoidal endothelial cells by chemotherapy agents.

Drugs that cause sinusoidal obstruction syndrome include alkylating agents busulfan, cyclophosphamide, and monoclonal antibody-cytotoxic conjugates.
I can also be caused by botanicals.

Decreased nitrous oxide production contributes to VOD associated it help maintain the hepatic microcirculation and endothelia integrity.

Onset typically is typically by day 35 after stem cell transplant.

Symptoms include abdominal pain, increased liver size, weight gain, jaundice, it appears 1 to 3 weeks after exposure and may progress rapidly to hepatic failure.
Histologic studies show dilatation of sinusoids and extravasation of red cells with hepatic cell necrosis in central areas.

Average mortality rate for severe disease is greater than 80%.

One of the main risk factors is pre-existing hepatic disease.

Risk is higher after allogeneic transplantation than after autologous transplantation, and higher in patients who are receiving a second transplant.

The risk is reduced in patients receiving reduced intensity conditioning regimens for hematopoetic transplant.

Younger age is associated with increased risk.

The process is a clinical syndrome and diagnosis includes development of hyperbilirubinemia, weight gain, the sidelines, and painful hepato-megaly.

Classic signs include ascites and painful hepatomegaly.

Commonly associated problems include thrombocytopenia, hypernatremia, increased abdominal girth, respiratory and renal dysfunction.

Can occur without hyperbilirubinemia.

May occur in non-HSCT settings.

Symptoms occur generally within 3-4 weeks after bone marrow transplant.

Symptoms manifest within 21 days after transplant.

Differential diagnosis includes: graft versus host disease, infections such as hepatitis, systemic sepsis, and cholangitis.

Cholestasis that occurs following parenteral nutrition can also be confused with VOD, as Kendra toxicity, fluid overload, and right heart failure.

Most patients experience mild to moderate disease while those with severe disease have a 100% mortality by day 100 after stem cell transplant.

Progression of disease is unpredictable, and this underscores the need for early diagnosis and monitoring of patients.

Symptoms may resolve in mild or moderate disease, but can progress despite supportive care.

Severe disease associated with multi organ dysfunction and typically affects the lungs and kidneys and mortality for this subset of patients can exceed 80%.

Risk factors include antecedent liver toxicity, viral hepatitis, and iron overload disorders.

Patients and high-risk include pediatric patients treated for neuroblastoma or osteopetrosis and those with low performance score.

Increased risk with antibody drug conjugates.

Increased risk with inotuzumab ozogamicin and gemtuzumab.

The risk is increased in patients treated with gemtuzumab or radiation to the liver.

The risk is higher with allogeneic transplants rather than autologous transplants.

The risk is higher with more intense chemotherapy regimens and particularly those that combine busulfan and cyclophosphamide.

Liver ultrasound is part of the diagnostic evaluation helping to exclude other diagnoses.

In VOD ultrasound can confirm ascites, hepatomegaly, and can demonstrate reversal of blood flow in the portal venous system.

Liver biopsy is usually reserved for patients with difficult to diagnose disease following clinical and radiologic data.

Evidence of sinusoidal obstruction, tissue injury, scarring fibrosis or necrosis can be observed histopathologically when the process is severe.

Plasminogen activator inhibitor type-1 increases in VOD.

Sirolimus administered in allogeneic BMT increases risk of VOD, especially when added to tacrolimus.

Management: early diagnosis, fluid, electrolyte, renal and respiratory care.

For moderate disease, fluid management is the treatment of choice to preserve kidney perfusion.

Removal of ascites may be required to improve breathing, but it should not be too aggressive to prevent renal insufficiency.

No consensus exists as to a preventative management.

Treatment is primarily supportive care.

For a mild disease which is self-limiting, it does not usually require any intervention.

Use of defibrotide lowers incidence of VOD, and can be used in moderate and severe disease.

Defibrotide should be used in patients who were at high-risk and are undergoing myeloablative conditioning.

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