Sinusoidal obstruction syndrome





Introduction


Sinusoidal obstruction syndrome (SOS) is a well-described complication of the high-dose conditioning regimens used in hematopoietic stem cell transplantation (HSCT), as well as certain hepatotoxic chemotherapies or radiation therapy used in other settings, and is a well-recognized cause of HSCT patient mortality. It was previously known as hepatic veno-occlusive disease based on the pathologic features, but the term was changed to SOS when it became clear that the initial injury is caused by changes in the hepatic sinusoidal cells. , The epidemiology of SOS is difficult to define because of differences in definitions and patient populations, and the clinical presentation ranges from mild, self-limited disease to severe SOS with multiorgan failure and mortality rates in excess of 80%. In recent years, there has been improvement in the understanding of the pathogenesis of SOS and new strategies for both prevention and treatment.




Epidemiology


Incidence


The incidence of SOS varies greatly in the literature, because of controversies in diagnosis, variable diagnostic criteria, and confounding factors, such as the patient population being studied. The published rates of SOS in all populations range from 0% to 60% of HSCT patients, but the mean incidence in a recent systematic review was 13.7%. The incidence of SOS clearly varies by type of transplant; rates in fully myeloablative allogeneic transplants are 10% to 60%, whereas in reduced-intensity conditioning regimens and autologous transplants, the incidence is much lower, ranging from 5% to 30%.


Adults


The average incidence of SOS in adults is 8% to 14% depending on the series and in a few studies is as high as 40%; this is much lower than observed in children. The incidence of SOS has steadied now that there is a greater emphasis on use of reduced intensity conditioning regimens.


Pediatrics


In contrast to adults, SOS is a common complication of HSCT in children, occurring in approximately 20% to 30% of patients overall and as many as two-thirds of those at high risk for this complication. One of the challenges of making this diagnosis in the pediatric population is the fact that one-third of children with SOS do not have hyperbilirubinemia; , therefore dependence on strict fulfillment of the Baltimore or modified Seattle criteria may miss the diagnosis, and children are more likely to present with late-onset SOS (20%). , , Pediatric patients who do develop hyperbilirubinemia usually do so late in their disease progression or as a manifestation of more severe SOS. An early diagnostic clue in the pediatric population is thrombocytopenia that is refractory to platelet transfusion; this usually precedes the diagnosis by 1 week. Children also can have more severe disease, with 30% to 60% developing multiorgan dysfunction. ,




Risk factors ( table 12.1 )


Patient related


Extremes of age increase the risk of SOS in both adults and children, , as does poor Karnofsky performance status (< 90%) , or dependence on parenteral nutrition before transplant. Advanced malignant disease, and the etiology of the underlying malignancy, are well-recognized risk factors. , In children, a diagnosis of osteopetrosis, familial hemophagocytic lymphohistiocytosis, juvenile myelomonocytic leukemia, thalassemia major, sickle cell disease, neuroblastoma, Wilms tumor, or rhabdomyosarcoma have all been associated with a higher risk of SOS. Laboratory abnormalities indicative of liver injury or inflammation, such as elevated transaminases, ferritin, or bilirubin, also are associated with a higher SOS risk. Several genetic mutations predisposing to the condition have been identified, including GSTM1-null, C282Y allele, and the MTHFR 677CC/1298CC haplotype. Patients with preexisting liver disease caused by viral hepatitis or iron overload are also at elevated risk for this complication. Although it had been suggested in the past that there may be a gender difference in SOS, the increased risk for SOS development seems to be limited to women maintained on norethisterone to prevent gynecologic bleeding.



Table 12.1

Risk factors for Development of Sinusoidal Obstruction Syndrome























































Pretransplant Transplant



  • Age < 1 year




  • Allogeneic > autologous




  • Increased transaminases




  • Haploidentical




  • Preexisting liver disease




    • Viral hepatitis



    • CMV positivity





  • Conditioning regimen




    • Busulfan



    • Busulfan + cyclophosphamide (Cy)



    • Fludarabine



    • Carmustine (BCNU) + Cy + etoposide





  • Underlying disease




    • MDS



    • Inborn errors of metabolism



    • Leukemia



    • CML



    • Immunodeficiency



    • Thalassemia





  • Total body irradiation > 12 Gy + Cy




  • Interval between diagnosis and HCT > 12 months




  • GVHD prophylaxis




    • Sirolimus + methotrexate _ tacrolimus



    • Methotrexate + cyclosporine



    • Cyclosporine





  • Deteriorating health pretransplant




    • Diarrhea



    • Fever



    • Parenteral nutrition





  • Non-T cell depleted grafts




  • Prior transplant




  • Peripheral blood > bone marrow




  • Prior abdominal radiation therapy




  • Acute hepatic or gut GVHD




  • Prior -ozogamicin agents




  • Prior norethisterone




  • Karnofsky index < 90%




  • GSTM1 null phenotype




  • Impaired pulmonary function




  • Infections/antimicrobials




    • Sepsis



    • Vancomycin



    • Acyclovir





  • Ferritin > 1000 ng/mL




  • Bilirubin > 26 μmol/L


CML, chronic myeloid leukemia; CMV, cytomegalovirus; GSTM1, glutathione transferase mu- 1; GVHD, graft-versus-host disease; Gy, units of gray; HCT, hematopoietic cell transplantation, MDS , myelodysplastic syndrome.


Pretransplant treatment related


There are several pretransplant treatment characteristics associated with an elevated risk of SOS, including prior abdominal or liver radiation and baseline abnormalities in transaminases or bilirubin. , , Certain salvage chemotherapies used in leukemia to control disease and allow patients to proceed to HSCT deserve special mention. There are two antibody-drug conjugates that contain the same toxin, ozogamicin, that have been associated with SOS. Gemtuzumab ozogamicin (anti-CD33) was previously used in acute myeloma leukemia patients and was associated with SOS. , In patients exposed to gemtuzumab ozogamicin before HSCT, the risk of SOS was increased and fatalities resulting from SOS noted. However, the use of the lower dose regimen may be associated with an acceptable SOS risk of around 8%. This agent was taken off the market because of lack of use and toxicity concerns, but has recently been reapproved at a new dose. Inotuzumab (anti-CD22) ozogamicin has been approved for the salvage treatment of acute lymphoblastic leukemia and is associated with a 17% risk of SOS after HSCT.


Transplantation related


In general, more intensive consolidating regimens and less well-matched transplants increase the risk of SOS. SOS is more common in fully myeloablative regimens than in reduced-intensity regimens, but has been described as a complication of autologous transplants. Use of fludarabine, cyclophosphamide, high-dose melphalan, and busulfan for consolidation have all been associated with SOS; intravenous administration of busulfan may decrease the risk because of improved pharmacokinetic profiling of the dose. High-dose or unfractionated total body irradiation increase SOS risk. Second HSCT transplant recipients are also at increased risk for SOS because of their larger cumulative chemotherapeutic and radiation burden.


Although SOS can occur in autologous SCT, it is much more common in allogeneic transplants. Unrelated donors, donors with a greater degree of human leukocyte antigen (HLA) mismatch, non-T cell depleted grafts, and peripheral blood stem cell transplants are all associated with an increased risk for development of SOS. , Posttransplant factors, such as choice of graft-versus-host disease (GVHD) prophylaxis, can also have an effect, with patients maintained on a calcineurin inhibitor, especially if given in combination with sirolimus and methotrexate, being at higher risk.




Clinical presentation


Patients present with volume overload, with ascites, and weight gain greater than 5% of baseline. They often have jaundice and painful hepatomegaly. Acute kidney injury is frequently a component and mimics the hepatorenal syndrome with hypotension, hyponatremia, and a low fractional excretion of sodium. Although most patients with SOS present with symptoms within the first 30 days of transplant, a subset of patients will develop late-onset disease. ,




Diagnostic criteria


There are two established clinical criteria for the diagnosis of SOS, the Baltimore and modified Seattle criteria ( Table 12.2 ). Recently, the European Society for Blood and Marrow Transplantation (EBMT) proposed updated criteria for adults and pediatrics to address the limitations of the Baltimore and modified Seattle criteria ( Table 12.3 ). The rationale for this update was multiple—there are now effective therapies for SOS, making prompt diagnosis critical, and advances in our understanding of risk factors and imaging techniques to aid in diagnosis. In addition, there is a growing recognition that “late” SOS is a more common presentation than previously thought and that pediatric manifestations of the disease differ significantly from those seen in adults.



Table 12.2

Clinical Diagnostic Criteria for Sinusoidal Obstruction Syndrome



















Modified Seattle criteria Baltimore criteria
In the first 20 days after HCT, ≥ 2 of the following: In the first 21 days after HCT, bilirubin ≥ 2 mg/dL plus ≥ 2 of the following
Bilirubin > 2 mg/dL Painful hepatomegaly
Hepatomegaly or pain in right upper quadrant Ascites
Weight gain (> 2% basal weight) Weight gain

HCT , Hematopoietic cell transplantation.


Table 12.3

Summary of British Committee for Standards in Haematology and British Society for Blood and Marrow Transplantation for the Diagnosis and Management of Sinusoidal Obstruction Syndrome








































Diagnosis Should be based on clinical criteria (modified Seattle or Baltimore)
Ultrasound may be helpful
Liver biopsy only in patients where SOS diagnosis unclear
If performed, liver biopsy should be transjugular
Risk factors Patients should be assessed pretransplant for risk factors, and managed when possible
Prophylaxis Defibrotide is recommended in children with risk factors
Defibrotide is suggested in adults with risk factors
Prostaglandin E1, pentoxifylline, heparin, and antithrombin are not recommended
Ursodeoxycholic acid is suggested
Treatment Defibrotide is recommended in children and adults
TPA and N-acetylcysteine are not recommended
Methylprednisone may be considered with caveat for infectious risk
Careful fluid management
Early involvement of critical care specialists

SOS , Sinusoidal obstruction syndrome; TPA , tissue plasminogen activator.


The modified Seattle criteria specify that within the first 20 days after transplant, a patient must have two or more of the following: bilirubin greater than 2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain (> 2% of baseline weight). The Baltimore criteria specify that within the first 21 days after transplant, a patient must have a bilirubin greater than 2 mg/dL plus two or more of the following: painful hepatomegaly, ascites, or weight gain (> 5% of baseline weight).


The new EBMT criteria for diagnosis of SOS in adults recognize two clinical entities: “classic” SOS and “late onset” SOS. Classic SOS by EBMT criteria presents within the first 21 days after transplant. Patients must have an elevated bilirubin level (≥ 2 mg/dL) and two of the following: painful hepatomegaly, weight gain more than 5% of baseline, or ascites. Late onset SOS is any patient with the classic presentation beyond day +21 or those with biopsy proven SOS; alternatively, any patient beyond day 21 after transplant with two or more of the following: bilirubin of 2 mg/dL or more, painful hepatomegaly, weight gain more than 5% of baseline, ascites, and hemodynamic or ultrasound findings suggestive of SOS (decrease in velocity or reversal of portal venous flow). Thrombocytopenia, although common in patients with SOS, is not an official part of the new diagnostic criteria.


The EMBT has also established new diagnostic criteria for children. In these criteria, there is no longer a time limitation for the onset of symptoms. Patients require any two or more of the following: unexplained and transfusion refractory thrombocytopenia, unexplained weight gain for 3 days despite diuretics or weight gain more than 5% of baseline, hepatomegaly, ascites, and rising bilirubin for 3 consecutive days or an absolute bilirubin of 2 mg/dL or more.




Differential diagnosis


The differential diagnosis of SOS includes hyperacute hepatic GVHD, autoimmune hepatitis, cholestasis of sepsis, biliary obstruction, infection including abscess or acute viral hepatitis, cholestasis caused by cyclosporine or tacrolimus, drug toxicity, iron overload, and right heart failure. ,




Diagnostic tests


Laboratory tests


Adult patients with SOS often have elevated transaminases, hyperbilirubinemia, prolonged prothrombin time, elevated international normalized ratio, and low serum albumin. Approximately one-third of pediatric patients with SOS do not have hyperbilirubinemia.


Biomarkers


Although the diagnosis of SOS remains a purely clinical one, there have been attempts to identify noninvasive biomarkers for the disease. Plasminogen activator inhibitor-1, an inhibitor of the fibrinolytic system, was one of the first biomarkers identified; levels increase in SOS patients concurrent with the rise in serum bilirubin. Levels of thrombomodulin, von Willebrand factor (vWF), and soluble intercellular adhesion molecule-1 have all been shown to be elevated early in patients with SOS maintained on sirolimus for GVHD prophylaxis. In one study, levels of vWF 1400 IU/mL or greater and thrombomodulin 100 ng/dL or greater on day +7 were 100% sensitive and specific for the diagnosis of SOS. Using quantitative mass spectrometry based proteomics, Akil et al. developed a diagnostic biomarker panel for SOS; suppression of tumorigenicity-2, angiopoietin-2, L-ficolin, hyaluronic acid, and vascular cell adhesion molecule-1 (VCAM-1) levels together were diagnostic of SOS with an area under the curve (AUC) of more than 0.81. These markers were able to identify patients at risk for SOS as early as the day of stem cell transplantation. In addition, L-ficolin, hyaluronic acid, and VCAM-1 levels predicted the severity of SOS disease with greater than 80% accuracy, when combined with clinical data.


Liver biopsy


Transjugular liver biopsy with portal pressure measurement can be used to make a definitive diagnosis of SOS. Classic biopsy findings include acinar zone 3 necrosis and a wedged hepatic venous pressure gradient more than 10 mmHg is highly suggestive of the diagnosis. However, liver biopsy is an invasive procedure with significant risks of bleeding and the possibility of misdiagnosis because of sampling error; therefore this approach is not commonly used.


Transient elastography


In much of general hepatology practice, liver biopsy has been supplanted by noninvasive measures of liver fibrosis, including transient elastography, which uses ultrasound waves to measure liver stiffness; this test is highly congruent with biopsy results, especially for patients with advanced fibrosis. , At least two studies have investigated the utility of transient elastography in the diagnosis of SOS in pediatric HSCT patients. In one study of 25 patients, five developed SOS. Elastography measurements preconditioning did not differ between the groups, but as early as day +5, there was a significant increase in measured liver stiffness in the patients who eventually developed SOS; SOS was diagnosed at day +14 to 19 among these patients on the basis of modified Seattle criteria. The authors report that a velocity increase of 0.26 m/s over the baseline reading on day +5 was 60% sensitive and 90% specific for SOS. A second pediatric study with 22 patients (four of whom developed SOS) noted similar findings; there was again no difference in baseline elastography among patients but those who developed SOS had an increase in liver stiffness 3 to 6 days before their clinical diagnosis. In the adult population, a pretransplant liver stiffness of greater than 8 kPa was associated with significant hyperbilirubinemia posttransplant and posttransplant liver dysfunction, suggesting a role for transient elastography in identifying patients at risk for SOS in whom prophylactic defibrotide could be considered.


Ultrasound


Although ultrasound findings are not part of the official diagnostic criteria, they can assist in making the diagnosis and are useful for ruling out other etiologies in the differential diagnosis. On ultrasound, patients can have ascites, hepatomegaly, gall bladder wall thickening, small portal vein diameter, elevated hepatic artery resistive index (> 0.75), or reversal of hepatic venous flow.


Disease severity grading


SOS can be classified as mild, moderate, or severe ( Table 12.4 ). Patients with mild SOS can be managed with supportive care and their disease is usually self-limiting; in one series, 9% of patients with mild SOS died of their disease. Those with moderate disease will benefit from analgesics, diuretics to manage fluid balance, and supportive measures; mortality in this group is around 25%. Patients with severe SOS often have renal dysfunction and/or multiorgan system failure, with attendant mortality rates upwards of 80%.



Table 12.4

A Proposed Grading System for Sinusoidal Obstruction Syndrome Severity





































Grade
Mild a Moderate a Severe a
Bilirubin (mg/dL) 2.0–3.0 3.1–5.0 > 5.0
Liver function < 3× normal 3–5× normal > 5× normal
Weight above baseline, % 2 2.1–5 > 5
Renal function Normal < 2× normal ≥ 2× normal
Rate of change, days Slow (6–7) Moderate (4–5) Rapid (2–3) b

a Two or more of following, b Or creatinine clearance ≤ 50%.



The EMBT, in addition to updating the diagnostic criteria for SOS, have also proposed an updated grading system for establishing the severity of disease in adults, which is modeled after the Common Terminology Criteria for Adverse Events reporting structure, ranging from grade 1 (mild) to grade 5 (death). This new system not only considers absolute laboratory values in grading disease severity, but considers the kinetics of laboratory and symptoms development; it also upgrades patients who are in between categories to a more serious classification of disease. The rationale for these changes was to prompt clinicians to institute therapy sooner, as earlier treatment with defibrotide has been associated with improved survival in SOS. Patients with mild disease have had a slow onset of symptoms, with bilirubin between 2 and 3 mg/dL, transaminases that are less than twice the upper limit of normal, weight gain less than 5%, and creatinine that is less than 20% above their baseline. Moderate disease has a quicker onset (5–7 days), with a bilirubin between 3 and 5 mg/dL, transaminases 2 to 5 times the upper limit of normal, weight gain between 5% and 10%, and no more than a 50% increase in serum creatinine. Patients with severe disease have a rapid onset, less than 4 days, with bilirubin in the 5 to 8 mg/dL range, with doubling in the past 48 hours, along with transaminases 5 to 8 times normal, weight gain less than10%, and creatinine may have doubled. Very severe disease is characterized by the presence of organ failure/dysfunction, with bilirubin greater than 8 mg/dL, transaminases eightfold above normal, more than 10% weight gain, and the need for renal replacement therapy.


There is also an updated EBMT severity grading scale for SOS in children, with disease states categorized as mild, moderate, severe, and very severe/multiorgan failure. In mild disease, liver function tests (LFTs; aspartate transaminase, alanine transaminase, and glutamate dehydrogenase) are ≤ 2 times the upper limit of normal, thrombocytopenia has been present for less than 3 days, there is minimal ascites, glomerular filtration rate (GFR) is 89 to 60 mL/min, and there is minimal to no oxygen requirement. In moderate disease, LFTs are 2 to 5 times normal, thrombocytopenia has been present for 3 to 7 days, there is moderate ascites, GFR is 59 to 30 mL/min, and supplemental oxygen is required. Severe disease presents with LFTs greater than 5 times normal, more than 7 days of resistant thrombocytopenia, bilirubin 2 mg/dL or more, ascites requiring paracentesis, coagulopathy, GFR 29 to 15 mL/min, and ventilatory support is required. Very severe disease is similar with doubling of bilirubin in 48 hours, replacement of coagulation factors, renal replacement therapy, and cognitive impairment.




Prognosis


The prognosis of SOS depends on the severity of disease. In patients with mild disease, it is often self-limiting and they will improve with minimal clinical intervention. Those with moderate disease often require supportive care to manage their fluid balance and clinical symptoms. Severe disease, especially if accompanied by renal or pulmonary failure, is often fatal with mortality rates in excess of 80%.

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Mar 16, 2020 | Posted by in NEPHROLOGY | Comments Off on Sinusoidal obstruction syndrome

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