Canterbury DHB

Veno Occlusive Disease of the Liver (VOD)

Pathogenesis

Veno-occlusive disease, also known as sinusoidal obstructive syndrome (SOS) is a life-threatening complication of HCT. It occurs typically before day 30 and is more common after allogeneic than autologous transplantation. It is thought to occur due to conditioning regimen-induced injury to the vascular endothelial cells in zone 3 of the liver resulting in activation of pro-inflammatory pathways, e.g. TNF. Extravasation of cells between the damaged endothelial cells leads to extraluminal compression of the sinusoids resulting in obstruction. Injury to the endothelial cells also triggers a pro-coagulant effect leading to further narrowing of the sinusoids. Hepatic venous outflow obstruction leads to portal venous flow reversal and hepato-renal syndrome.

Clinical Features and Diagnosis

A clinical syndrome of raised bilirubin, enlarged liver, ascites and fluid retention post SCT with an onset usually by day +30.

The differential diagnosis includes hyperacute GvHD, cholestasis of sepsis, medication, biliary obstruction and fungal abscess.

USS may be useful and is non-invasive but should not delay treatment. Findings that suggest VOD are ascites, reversal of portal flow, hepatic artery resistance index 0.75 and abnormal portal vein waveform.

Liver biopsy is technically difficult and has a high rate of complications in this patient population but if required should be performed by an interventional radiologist using the trans-jugular approach. It is not performed routinely.

Grading of VOD

From Chao, N. (2014). "How I treat sinusoidal obstruction syndrome." Blood 123(26): 4023-4026.

Prognosis

Mild to moderate VOD usually resolves completely with supportive treatment including symptom control and diuretics.

The day +100 mortality in severe VOD with multi-organ failure is approximately 80% with a strong correlation with response to treatment. Non-responders have a day +100 mortality of approximately 90%.

Management of VOD

Prophylaxis

• Ursodiol 250 mg TDS for all patients undergoing myeloablative conditioning and other patients considered high risk.
• Defibrotide is recommended by the BCSH/BSBMTguideline for patients at high risk but is not currently funded in NZ for prophylaxis.
• Avoid paracetamol, posaconazole, voriconazole, itraconazole, and metronidazole for 72 hours before and after busulfan because these can increase plasma levels and increase the risk of VOD.

Very high risk patients for VOD include:

• Pre-existing hepatic disease
• Second myeloablative transplant
• Leukaemia beyond 2nd relapse
• Busulphan containing conditioning regimens
• Prior treatment with gemtuzumab
• Primary haemophagocytosis, adrenoleucodystrophy and osteopetrosis

Monitoring

• Clinical assessment for fluid overload, ascites, abdominal tenderness and hepatomegaly.
• Daily measurement of liver function and weight.

Treatment

Other treatments

Thrombolytic therapy, prostacycline, prednisone, anti thrombin III and activated protein C are all ineffective and/or carry unacceptable side effects. Porto-systemic shunts also carry high risks. Liver transplantation has been used successfully in patients severely affected by VOD but who have an otherwise good prognosis.

Further reading

• Richardson, P. G., et al. (2013). "Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions." Biol Blood Marrow Transplant 19(1 Suppl): S88-90.
• Chao, N. (2014). "How I treat sinusoidal obstruction syndrome." Blood 123(26): 4023-4026.
• Dignan, F. L., Wynn, R. F., Hadzic, N., Karani, J., Quaglia, A., Pagliuca, A., Veys, P., Potter, M. N. (2013), BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. British Journal of Haematology, 163: 444–457. doi: 10.1111/bjh.12558

Topic Code: 9084