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Sinusoidal Obstruction Syndrome (SOS)

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Shared care information

This complication is unlikely to occur in a shared care centre. If concerns arise, please discuss them with the paediatric oncologist on call.

What is Sinusoidal Obstruction Syndrome (SOS)?

Sinusoidal obstruction syndrome (SOS), formerly known as Hepatic Veno-occlusive disease (HVOD), is a congestive hepatopathy with an acute severe form and a more chronic milder form that may manifest as disproportionate thrombocytopenia. A late sequel of SOS is non-cirrhotic portal hypertension.

It most commonly occurs after haemopoietic stem cell transplantation (myeloablative allogeneic>autologous or reducted intensity) and occasionally:

  • in Wilms' tumours or Rhabdomyosarcomas treated with Actinomycin-D
  • with 6-thioguanine.

The pathogenesis of SOS is poorly understood. Injury to the hepatic sinusoidal endothelial cells and hepatocytes appears to be the initiating event, leading to:

  • activation of the coagulation cascade with intrasinusoidal clotting and platelet consumption
  • sinusoidal obstruction, leading to
  • hepatocellular damage.

Factors that may influence the genesis of SOS include elevated homocysteine levels from MTX, concomitant administration of vincristine, CMV and other viruses, and genetic polymorphisms of enzymes.

Risk factors

  • pre-existing liver dysfunction - elevated AST
  • chemotherapy regimen:
    • myeloablative therapy with high doses of alkylating agents
    • Busulphan and cyclophosphamide conditioning - it is postulated that busulphan depletes hepatic glutathione, and cyclophosphamide metabolites (acrolein and 4-OH-cyclophosphamide) have a direct toxic effect on hepatic sinusoidal epithelium. Rates of HVOD are higher after Bu/Cy than after Cy/TBI.
    • very high-dose cyclophosphamide
    • actinomycin-D and Wilms' tumour (occasionally described in rhabdomyosarcoma). Vincristine is an additional risk factor here.
    • 6-thioguanine
    • Gemtuzemab (this has recently been withdrawn from use in the USA and its ongoing use in paediatric protocols is uncertain)
    • Prior abdominal radiotherapy
    • Age at SCT < 6.5 years.

Clinical presentation

Early diagnosis

In the early stages the classic diagnostic triad (see below) is often not present. Relative platelet refractoriness with a mild elevation of hepatic enzymes may be the only signs. This may worsen or settle but the risk of development of SOS with a subsequent course of treatment if there has been prior SOS is ~ 75%.

Clinical features

The classic clinical criteria (Jones' criteria) are:

  • jaundice Br > 34 mmol/L

    and two of:
  • painful hepatomegaly
  • weight gain > 5% above baseline
  • ascites.

Other features include:

  • raised ALT and AST
  • refractoriness to platelet transfusions
  • usually occurs within 30 days of transplant or within a week of receiving more conventionally-dosed chemotherapy
  • liver failure and coagulopathy
  • hepatorenal syndrome - fractional excretion of sodium falls sharply just before the onset of overt SOS and explains the rapid weight gain.
  • disproportionate thrombocytopenia may indicate "low-grade" SOS and risk of portal hypertension.

Wilms' Tumour

The risk of SOS is of the order of 4 - 10%, particularly with infants and when pre-operative chemotherapy is given.

It may occur in a fulminant form with sudden onset of abdominal distension and pain. This may mimic tumour rupture so patients should always be scanned prior to any surgical intervention. It may also be mild with mild elevation of liver enzymes and disproportionate thrombocytopenia.

Investigations

The diagnosis is essentially a clinical one.

Radiology

Ultrasound, MRI and CT will all show the hepatomegaly, ascites, as well as oedema of the gallbladder wall. While doppler ultrasound showing reversal of portal venous flow is diagnostic, it is usually only present at the late stages of the disease and its absence does not exclude SOS.

Liver biopsy

This is obviously dangerous in the setting of coagulopathy and should only be considered when there is doubt about diagnosis. Transvenous (femoral or jugular) biopsy is preferable because it reduces the risk of severe haemorrhage.

Prevention and management

Prevention

Defibrotide
This agent is a polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, anti-ischaemic and anti-inflammatory properties without producing systemic anti-coagulation.

Thought to operate through adenosine receptor agonist activity modulating thrombin and thrombomodulin. Adverse effects are usually mild and include hypotension, dizziness, headache, fever, nausea, epigastric pain and flushing.

It has recently been shown to reduce rates of SOS in the paediatric transplant setting by 40% when used prophylactically2. It is approved for treatment of SOS in New Zealand and approval for prophylactic use is awaited.
Ursodiol
Ursodeoxycholic acid (Ursodiol) is a hydrophilic water-soluble bile acid that has been shown to reduce the incidence of hepatic complications and improve overall survival post SCT.

In addition to stabilising the hepatocyte cell membrane, ursodiol reduces release of inflammatory cytokines such as TNF and interleukins. Adverse effects include headache, fatigue, anxiety, GIT symptoms including constipation and flatulence, rashes and myalgia. The dose is 300 mg/m2/day in 2 - 3 divided doses from start of chemotherapy to day +80 (for BMT).
Busulphan levels
Pharmacokinetic monitoring of busulphan levels - this is routinely done with doses modified to maintain an AUC between 900 - 1400 mcmol/min. Dose modification reduces the incidence of HVOD.

Treatment

General

  1. Treat ascites, jaundice, etc., as for hepatic failure (eg K+-sparing diuretic, low protein diet, non-absorbable oral antibiotics).
  2. Platelet transfusions should be limited as supplementing platelets increases sinusoidal obstruction.
  3. Maintain intravascular volume. Fluid balance may be hard to assess due to the fluid accumulation with SOS but aggressive diuretic therapy may deplete intravascular volume predisposing to "sludging" within hepatic sinusoids.

Severe cases

  1. The outcome is better when treatment is started early. Disproportionate thrombocytopenia, platelet refractoriness and enlarged, tender liver are the early clues.
  2. Defibrotide is now first line therapy. The current recommended dose is 25 mg/kg/day IV. Average duration of therapy is 17-21 days. The average delay from diagnosis to initiating therapy is significantly shorter for those achieving CR (1.6 vs 4.6 days).
  3. Several other therapies have been proposed for SOS, however, currently these are at the discretion of the treating clinician as evidence for efficacy and safety is lacking.

Mild/moderate cases

  1. Ongoing supportive care measures listed above may be all some patients require until the disease runs its course for patients who are not requiring platelet transfusions or showing signs of rapidly progressive liver dysfunction.

References

  1. Ho VT, Revta C, Richardson PG. Hepatic veno-occlusive disease after haematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. BMT;2008;41:229-237.
  2. Corbaclioglu et al. Defibrotide prevents hepatic VOD and reduces significantly VOD-associated complications in children at high risk: final results of a prospective phase II/III multicenter study, EBMT annual meeting 2010.

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Document Control

  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network