Sinusoidal obstruction syndrome

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious and potentially fatal complication most commonly seen after hematopoietic cell transplantation (HCT). This condition is characterized by hepatic venule obstruction that leads to sinusoidal congestion and hepatic ischemia. Fulminant liver failure may occur in severe cases. Key causes include allogeneic HCT and myeloablative conditioning regimens. Pre-existing liver disease is a risk factor. The classic clinical presentation is a triad consisting of painful hepatomegaly, jaundice, and fluid retention with weight gain, typically appearing within 21 days of HCT. Diagnosis is primarily clinical, based on established criteria, and is supported by laboratory findings (e.g., hyperbilirubinemia) and imaging studies (e.g., Doppler ultrasound). Management focuses on supportive care, including careful fluid balance and avoidance of hepatotoxic agents. For moderate to severe cases, defibrotide is the standard of care. Prophylaxis with ursodeoxycholic acid is recommended for all patients undergoing HCT. The prognosis is highly dependent on the severity of the disease and the timeliness of intervention, with severe cases involving multi-organ dysfunction carrying a mortality rate exceeding 80%.

• Worldwide incidence after HCT: ∼ 10% in adults and ∼ 20% in children ^[1]
• Incidence after allogeneic HCT ^[2]
  • With myeloablative conditioning: ∼ 10–15% ^[2]
  • With reduced-intensity conditioning: up to 5% ^[3]
• Incidence after autologous HCT: < 5% ^[2]

Epidemiological data refers to the US, unless otherwise specified.

Toxic injury to endothelium of sinusoids and venules (from, e.g., myeloablative high-dose chemotherapy, liver radiation, pyrrolizidine alkaloids) → initiation of coagulation cascade → embolism formation (fibrin, cellular debris) → progressive obstruction of sinusoids → intrahepatic post sinusoidal portal hypertension

• Typical presentation ^[1][4]
  • Hepatomegaly
  • Right upper quadrant pain
  • Jaundice (due to hyperbilirubinemia)
  • Weight gain (due to fluid retention)
  • Ascites
• Timing of onset ^[5]
  • Classical SOS/VOD: occurs ≤ 21 days after HCT ^[2]
  • Late-onset SOS/VOD: occurs > 21 days after HCT

• Severity is classified using the European Society for Blood and Marrow Transplantation (EBMT) grading criteria for SOS/VOD.
• Cases are classified into the most severe category for which they meet ≥ 2 criteria.
• SOS/VOD in patients with multi-organ dysfunction is automatically classified as very severe.

The diagnosis is based on clinical criteria, supported by laboratory and imaging findings, after excluding other causes of liver dysfunction.

Supportive diagnostic studies ^[5][6]

Laboratory studies

• Total bilirubin ≥ 2 mg/dL ^[6]
• Other biomarkers that may support the diagnosis include:
  • ↑ D-dimer
  • ↓ Antithrombin III
  • ↑ von Willebrand factor

Imaging

• Doppler ultrasound findings may include:
  • Reduction or reversal of portal venous flow
  • Monophasic or attenuated hepatic venous waveforms
  • Increased portal pulsatility
  • Increased hepatic artery resistance index (> 0.8) ^[6]
  • Hepatomegaly and/or splenomegaly
  • Ascites
  • Diffuse hepatic hyperechogenicity
• Elastography: Liver stiffness measurement can be used to assess for hepatic congestion.

Biopsy

• Transjugular liver biopsy is the gold standard for diagnosis.
• Rarely performed due to the high risk of bleeding

Diagnostic criteria ^[5][6]

Probable SOS/VOD ^[5]

Diagnosed if ≥ 2 of the following criteria are present:

• Total bilirubin ≥ 2 mg/dL
• Painful hepatomegaly
• Weight gain > 5% from baseline
• Ascites
• Ultrasound and/or elastography findings that suggest SOS/VOD

Clinical SOS/VOD ^[5]

Diagnosed in patients with bilirubin ≥ 2 mg/dL and at least two of the following:

• Painful hepatomegaly
• Weight gain > 5%
• Ascites

Proven SOS/VOD

Diagnosis is confirmed with at least one of the following:

• Histological confirmation via biopsy
• Hepatic venous pressure gradient ≥ 10 mm Hg

• Budd-Chiari syndrome
• Isolated acute hepatic graft-versus-host disease (GVHD)
• Other causes of acute liver failure
• Hepatic fungal infiltration
• Acute viral hepatitis
• Cholangitis lenta
• Drug-induced liver disease
• Constrictive pericarditis and right congestive heart failure
• Persistent tumor infiltration of the liver
• Parenteral nutrition-associated liver injury
• Hemolysis

The differential diagnoses listed here are not exhaustive.

Pharmacotherapy ^[6]

• Agent: Defibrotide
• Indications ^[1][3]
  • Standard of care for severe or very severe SOS/VOD
  • Consider for patients with moderate SOS/VOD.
  • Early administration is crucial to improve outcomes.
• Duration: at least 21 days and until complete resolution of symptoms ^[6]
• Monitoring ^[6]
  • Monitor for signs of bleeding.
  • Monitor coagulation parameters (e.g., prothrombin time, aPTT, fibrinogen), liver function, and renal function.

Supportive care ^[1][3][6]

• Careful management of fluid and sodium balance
  • Twice-daily weight monitoring
  • Sodium restriction
  • Strict monitoring of intake and output
  • Diuretics for fluid overload
• Avoidance of hepatotoxic and nephrotoxic medications
• Symptom management
  • Opioid analgesics for pain
  • Drainage of ascites or pleural effusions
• Management of complications, e.g.:
  • Renal replacement therapy (e.g., hemodialysis) for renal failure
  • Early transfer to an intensive care unit for multi-organ dysfunction management
  • Transjugular intrahepatic portosystemic shunt (TIPS) for portal pressure reduction
• Consider maintaining higher transfusion thresholds (e.g., platelets > 30,000/mm³, hemoglobin > 8.5 g/dL). ^[6]

• Address modifiable risk factors before HCT (e.g., treat active hepatitis, optimize conditioning regimen). ^[1]
• Pharmacoprophylaxis
  • Ursodeoxycholic acid: recommended for all patients undergoing HCT, starting before conditioning and continuing for 90 days after HCT. ^[1][3]
  • Defibrotide: may be considered for prophylaxis in adult patients at very high risk of SOS/VOD ^[3]

• Multi-organ dysfunction with, e.g.: ^[2]
  • Renal dysfunction or failure
  • Pulmonary dysfunction or failure
  • Encephalopathy
• Sepsis ^[4]
• Pneumonia ^[4]
• Bleeding ^[4]

We list the most important complications. The selection is not exhaustive.

• The prognosis is highly dependent on early diagnosis and intervention. ^[6]
• Severe forms of SOS/VOD with multi-organ dysfunction have a mortality rate > 80%. ^[2]
• In one study, the application of the revised EBMT 2023 criteria led to a 34% increase in 100-day survival for patients diagnosed early. ^[6]
• The prognosis is significantly worse for patients who progress from probable to clinical SOS/VOD. ^[6]