This fairly rare complication has received a level of attention from the CICM examiners which is out of proportion to its prevalence in clinical practice. It would be rare to see this unless one works in a centre where many bone marrow transplants are performed. In spite of its exotic nture, VOD has appeared in  Question 13.2 from the first paper of 2015,  Question 26.2 from the first paper of 2013 and the identical  Question 22.1 from the second paper of 2008.

Diagnosis of veno-occlusive disease

Clinical features

  • Early in the post-transplantation period (first 3 weeks)
  • Oedema and hyponatremia
  • LFT derangement
  • Jaundice
  • Firm painful hepatomegaly
  • Ascites
  • 50% will develop renal failure; 25% will go on to require haemodialysis
  • Thrombocytopenia is described as an early sign, but these are BMT patients and they are almost always thrombocytopenic anyway.

Diagnostic criteria

The college presents their exam candidates with a scenario of a bone marrow transplant recipient whose LFTs have suddenly become deranged. In addition to this, some pressure variables are listed (right atrial pressure and portal venous pressure). This is weird, because pressure measurements are not diagnostic of VOD.  There are the Seattle criteria and there are the very similar Baltimore criteria, neither of which actually mention any pressures at all - they demand hepatomegaly, ascites and raised bilirubin. The pressure values are given in the SAQ so that the candidates can confidently exclude cardiac congestive hepatopathy.

Seattle criteria:

  • Two or more of the following:
    • Bilirubin > 34mmol/L
    • Hepatomegaly
    • RUQ pain
    • Weight gain >2%
  • Within 20 days of BMT

Baltimore criteria:

  • Bilirubin > 34mmol/L,
    AND two or more of the following:
    • Hepatomegaly
    • Ascites
    • Weight gain >5%
  • Within 21 days of BMT

One pressure variable which might be of use is the  hepatic venous pressure gradient, which would require a WHVP (wedged hepatic venous pressure). You never end up measuring this variable unless you are performing a transjugular venous liver biopsy. This gradient is the difference between the wedged hepatic venous pressure and free (unwedged)  hepatic venous pressure. The wedged pressure approximates the portal venous pressure, in a similar sense as PAWP approximates LA pressure. If the gradient is greater than 10mmHg (i.e. the free hepatic venous pressure is 10mmHg lower than the portal pressure) then there is obviously some sort of obstruction to flow, which is the veno-occlusive disease.

Diagnosis does not require ultrasound, but it is usually ordered in this context. The BCSH/BSBMT guidelines (2013) concluded that "the main role of ultrasound is to exclude the presence of other diagnoses" because the ultrasound findings which are usually associated with VOD are insufficiently sensitive and specific. In any case, here they are:

  • Ultrasound-confirmed ascites
  • Ultrasound-confirmed hepatomegaly
  • Splenomegaly
  • Attenuated or reversed hepatic venous flow
  • Thickened gallbladder wall
  • Ultrasound evidence of increasing hepatic artery  vascular resistance (there is a "hepatic artery vascular resistance index",  which is helpful in the diagnosis if it is greater than 0.75.)

 

Management of veno-occlusive disease

Prevention

  • A recent meta-analysis of interventions (Cheuk et al, 2015) has suggested some of the following:
    • Minimise exposure to hepatotoxic agents
    • Reduced intensity conditioning protocol
    • Tacrolimus and methotrexate instead of sirolimus (higher risk with sirolimus)
    • Ursodeoxycholic acid prophylaxis (among the published evidence, this has the strongest support)
    • Low dose IV heparin, continuing until engraftment

Rescue therapy

  • The current BCSH/BSBMT guidelines suggest the following management options:
    • Defibrotide
    • Methylprednisolone
    • Careful fluid management (which means basically diuretics and fluid restriction)
    • TIPS
    • Liver transplant

 

References

Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.

Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.

Richardson, Paul G., et al. "Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial." Biology of Blood and Marrow Transplantation 16.7 (2010): 1005-1017.

Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.

Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.

Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.

Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.

Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.

Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.

Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.

Cheuk, D. K., et al. "Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation." The Cochrane database of systematic reviews 5 (2015): CD009311-CD009311.

Mohty, M., et al. "Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation." Bone marrow transplantation 51.7 (2016): 906-912.