Hepatic Sinusoidal Obstruction Syndrome in the Era of Defibrotide

  

    

    
Mild 
    
Moderate 
    
Severe 
  
  

    
Bilirubin, mg/dL
    
<5
    
5.1- 8
    
>8
  
  

    
Liver function
    
<3× normal
    
3-8× normal
    
>8× normal
  
  

    
Weight above baseline
    
<2%
    
2-5%
    
>5%
  
  

    
Renal function
    
Normal
    
<2× normal
    
>2× normal
  
  

    
Rate of change
    
Slow
    
Moderate
    
Rapid
  

Table 2:  Grade of SOS.

Supportive care: Adequate fluid and sodium balance for intravascular volume maintenance and renal perfusion with restriction of salt and water intake, and avoidance of hepato- and nephrotoxic drugs are the initial measures. Diuretics could be carefully added if weight-gain progresses despite these basic measures [9,14,16,18].

Analgesia is really requisite management. Frequently narcotic type analgesics can suppress the pain.

Paracentesis, thoracentesis, oxygen therapy are other rarely needed supportive treatments. If needed, ascites removal must be in small daily quantities, to avoid renal flow reduction.

Low dose dopamine, haemodialysis, haemofiltration and mechanical ventilation may also be symptomatic measures.

Anticoagulation: Protein C concentrate is with some beneficial effect. Antithrombin III has also shown efficacy. Recombinant human tissue plasminogen activators (rt-PA 0.05 mg/kg/h during 4 hours; maximum 10 mg/day 2–4 days ± sodium heparin 20 U/kg as a bolus (maximum 1000 U) followed by 150 U/kg/day by continuous infusion for 10 days) are effective in less <30% and with high bleeding risk. rt-PA has been shown to be effective only in patients with a non-advanced SOS. Its use is contraindicated in patients with multi- organ dysfunction syndrome (MODS), haemorrhages or severe hypertension [19].

Steroid therapy: Corticosteroids are potent cytokine inhibitors and therefore may have a role in the treatment of SOS. High-dose steroid therapy consisted of intravenous methylprednisolone 500 mg/ m² per dose every 12 hours for six doses, followed by a taper to 2mg/ kg/day for 3 days, and subsequently tapered per treating physician preference. Recommendations for steroid therapy is initiating at or before first ultrasound evidence of reversal of portal venous flow. Steroid therapy is easily available at any institution with known expected side effects and standard monitoring which make it distingue but further prospective clinical trials are required to assess the true efficacy of high-dose steroid therapy for post-HSCT SOS [20].

Defibrotide therapy: DF is a sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosa DNA. The probable mechanism of DF action is anti-inflammatory, anti-thrombotic and anti-apoptotic effects on endothelial cells. The efficacy of DF for severe SOS was first demonstrated in a retrospective dose escalation study (doses ranging 5 to 60 mg/kg) that include 19 patients. Resolution of SOS was observed in eight patients (42%), six of whom survived longer than 100 day which was followed by several studies [21,22]. In general, DF provides resolutions of symptoms in nearly half of the patients with the recommended dose 25 mg/kg/day. It is recommended usually in severe SOS as started immediately whereas delay in starting decreases of complete response rate [23]. DF is well tolerated: 22% of patients experienced at least one adverse event, which primarily consisted of hemorrhage (17%) and hypotension (4%) [24]. In a pediatric patient’s study, it was documented that prophylaxis with DF for SOS leads to a delay to the engraftment of polymorphonuclear neutrophils and white blood cells [25].

Duration of DF: DF should be continued at least 3 weeks and until the patient’s all symptoms resolved. For patients with severity of less then severe SOS, 14 days of treatment may be sufficient.

Transjugular intrahepatic portosystemic shunt (TIPS): TIPS is the procedure to decompress the portal circulation [26].

Liver transplantation: Patients’ who are expected to have a good outcome in the absence of liver disease could be liver transplant candidates [27].

Risk factors, prevention and prophylaxis

SOS can be with fatal outcome. The primary goal should be to identify patients with high risk for SOS development and implement efforts to prevent SOS. The pathophysiology of SOS is related mainly with damage to the hepatic endothelial cells venules [28]. Injured endothelial cells express cytokines such as tumor necrosis factor-α, interleukin-6, and endothelin-1 that cause hypercoagulability and inflammatory cell infiltration. VCAM-1, P-selections, and intercellular adhesion molecule 1 (ICAM-1) are other expressing molecules. PAI- 1, stimulated by transforming growth factor β (TGF-β) which was released from activated platelets, elevates as a marker of endotelial injury [29,30]. Endothelial cell injury increase with cytokines and cytokines increase with injury thus creating a vicious cycle toward SOS. Marked depletion of glutathione in subendotelial cells that precedes cell death, decreased nitric oxide levels due to decrease in hepatic flow and increase of matrix metalloproteinase-9 and 2 are the other factors that participate to this cycle [31,32]. Fibrin deposition, clot formation, extravasation of red blood cells and leukocytes into the space of Disse, narrows the sinusoids, causes portal hypertension and reduces the hepatic venous outflow. Liver enlarges with capsular distension which is sensed clinically as right upper qudrant pain.

The incidence of SOS is related to the presence of several risk factors (Table 3). The incidence of SOS after autologous HSCT is 5% it comes out up to 60% after allogeneic HSCT [33]. While the increased incidence of SOS in the allogeneic HSCT is associated with alloreactivity and hepatotoxicity of some drugs used in the conditioning regimen [34]. The haemochromatosis C282Y allele was also reported as a genetic predisposition for SOS [33].

  

    
Patient related 
    
 
  
  

    
Age
    
Younger < older
  
  

    
Sex
    
Male < female
  
  

    
Karnofsky Index
    
100 – 90 < lower than 90
  
  

    
Diagnosis
    
Non-malignancy <malignancy    < some malignancy
  
  

    
Status of disease
    
Remission < relapse
  
  

    
AST level    before HSCT
    
Normal < high
  
  

    
Previous liver radiation
    
No < Yes
  
  

    
Liver status
    
Normal < fibrosis, cirrhosis
  
  

    
Iron overloa
    
Absent < present
  
  

    
CMV serology
    
Negative < positive
  
  

    
Previous drugs
    
Gemtuzumab ozogamicine
  
  

    
Concomitant    drugs
    
Progestogens, ketoconazole,    cyclosporine, tacrolimus, methotrexate, amphotericin B, vancomycin, acyclovir
  
  

    
Genetic polymorphisms
    
GSTM1 or GSTT1, among others
  
  

    
Transplant    related 
    
 
  
  

    
Type of HCT
    
Syngeneic/autologous <    allogeneic
  
  

    
Type of    donor
    
HLA identical sibling <    unrelated
  
  

    
Grade of compatibility
    
Match < minor-mismatch <    majormismatch
  
  

    
T-cell in    the graf
    
T-cell depleted < non T-cell    depleted
  
  

    
Conditioning regimen
    
 
  
  

    
TBI
    
Fractionated < single dose    Low dose-rate < high dose-rate Less than 12 Gy < more than 12 Gy
  
  

    
Total dose
    
Cy alone < Cy-TBI < BVC    RIC < MAC
  
  

    
Busulfan
    
Intravenous < oral dose    targeted < oral non adjusted
  
  

    
Order of administration
    
Other combinations <    Busulfan
  
  

    
Timing
    
Cy to TBI 36 h < Cy to TBI    12 h
  
  

    
GvHD prophylaxis
    
CNI < CNI + sirolimus
  
  

    
HCT number
    
First < second HSCT
  

Table 3:  Risk factors for sinusoidal obstruction syndrome after HCT.