Version May 2024
INTRODUCTION — Hepatic sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD), is a systemic endothelial disease that typically presents in the days or weeks after hematopoietic cell transplantation (HCT) with refractory thrombocytopenia, hepatomegaly, ascites, and jaundice, and it can rapidly progress to multiorgan dysfunction and death. Rarely, SOS can arise after other causes of liver injury. A high index of suspicion is needed to diagnose hepatic SOS, and effective management is critical for reducing the associated morbidity and mortality.
The incidence, risk factors, clinical presentation, evaluation, and diagnosis of hepatic SOS differ between adults and children. This topic discusses SOS in adults.
Hepatic SOS in children is discussed separately. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in children".)
EPIDEMIOLOGY — Hepatic SOS, which is also called veno-occlusive disease (VOD), develops in up to 15 percent of adults after hematopoietic cell transplantation (HCT). The incidence of SOS varies with the patient population, aspects of transplantation, prior treatments, and predisposing risk factors. The reported incidence also differs because of evolving diagnostic criteria and variable levels of recognition and documentation [1].
The mean incidence of hepatic SOS was 14 percent (3425 cases among nearly 25,000 transplants in adults and children) in a review that analyzed 135 studies from 1979 to 2007 [1]. Rates differed between studies, in part, because of various diagnostic criteria, but few studies reported incidence >40 percent.
The incidence of SOS in adults appears to be relatively stable over recent decades [1-6]. This may reflect offsetting effects of lower-risk conditioning regimens and improved graft-versus-host disease management versus more transplants in older or heavily pretreated patients, who are more likely to have pre-existent liver injury.
Risk factors for hepatic SOS are discussed below. (See 'Risk factors' below.)
RISK FACTORS — Risk factors for hepatic SOS after hematopoietic cell transplantation (HCT) include pretransplant patient characteristics (eg, prior liver disease) and transplantation-related factors (eg, conditioning regimen, graft source, graft-versus-host disease [GVHD] prophylaxis regimen) (table 1). The odds ratios for various risk factors differ between studies [2,7,8].
Patient characteristics — The risk for hepatic SOS is increased in patients with pre-existent liver or lung disease, impaired performance status, and certain underlying diseases [6].
●Liver disease – Patients with pre-existent liver disease are at substantially increased risk for hepatic SOS [2,6,7,9-14]. In the largest series, the risk of developing SOS was 3 to 10 times greater in patients with increased serum aspartate aminotransferase (AST) prior to transplantation [7]. Patients with cirrhosis are at great risk for developing SOS, and most are considered ineligible for myeloablative HCT. (See "Determining eligibility for autologous hematopoietic cell transplantation" and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
It is unclear if the increased risk for SOS is linked to specific causes of liver disease. Patients who are seropositive for hepatitis B surface antigen and only mild or no elevations in liver enzymes are at increased risk for reactivation of the virus and GVHD but may not have an increased risk of SOS [15]. The risk in association with hepatitis C has been inconsistent [16-20]; it is unclear if effective antiviral treatment reduces that risk. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Lung disease – Reduced diffusion capacity (eg, <70 percent of predicted) was an independent risk factor for severe SOS in a study of 307 patients who underwent HCT; this may reflect pre-existing systemic endothelial cell damage and greater susceptibility to liver injury from chemotherapy [21].
●Other – Other pretransplant characteristics that are associated with risk for SOS are:
•Increased age [6].
•Performance status – Poor baseline performance status or declining health status [2,4,5].
•Underlying disease – Leukemias, including chronic myeloid leukemia [6,22,23].
Aspects of transplantation — Transplantation-related factors that have been associated with increased risk for hepatic SOS include:
●Preparative regimen – Myeloablative conditioning with certain alkylating agents (eg, busulfan, cytarabine, cyclophosphamide) is associated with a two- to eightfold increased risk for SOS [7,10,24-35]. Radiation therapy ≥12 gray (Gy) is associated with an increased risk of hepatic SOS, especially when administered in a single dose rather than using fractionated dosing [11,36-38]. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Hepatic vascular injury'.)
●Graft source – The risk of SOS is generally higher with allogeneic grafts than autologous grafts, but this may be primarily related to the degree of alloreactivity (ie, higher risk with an unrelated donor, HLA-mismatched donor, or non-T cell depleted graft) [1,2,39,40]. It is presently unclear if there is increased risk associated with HLA-haploidentical donors.
●GVHD prophylaxis – Certain GVHD prophylaxis regimens, including use of sirolimus in patients receiving cyclophosphamide/total body irradiation and methotrexate used with busulfan- or high dose etoposide-containing conditioning regimens, are associated with increased risk for SOS [22,41-43].
Other causes of SOS — Recent treatment with monoclonal antibodies conjugated with calicheamicin (eg, gemtuzumab ozogamicin, inotuzumab ozogamicin) are associated with a substantially increased risk (up to 20-fold) in patients who subsequently undergo HCT [44-47].
Other nontransplant-associated causes include chemotherapy (eg, oxaliplatin) [29], ingestion of pyrrolizidine alkaloids from herbal sources (eg, bush tea) [48], high dose radiation to the liver (usually >30 Gy) [49,50], radioembolization of liver tumors [51], and liver transplantation [52,53]. (See "Hepatotoxicity due to herbal medications and dietary supplements".)
PATHOGENESIS — Hepatic SOS is initiated by injury to sinusoidal endothelial cells, which is amplified by a local inflammatory response and activation of coagulation and fibrinolytic pathways, causing liver necrosis in severe disease.
The cellular injury is thought to be initiated by toxic metabolites generated by alkylating agents in conditioning regimens, ionizing radiation, or hepatotoxins [4,54]. These products damage sinusoidal endothelial cells and hepatocytes in the hepatic acinus, which creates gaps in the sinusoidal barrier through which cells and cellular debris pass into the space of Disse beneath the endothelial cells. The narrowed venous lumen reduces sinusoidal venous outflow, causes post-sinusoidal portal hypertension, and leads to widespread zonal liver disruption and centrilobular hemorrhagic necrosis. The process is compounded by cell damage from locally-released cytokines and activation of the coagulation and fibrinolytic pathways. Patients with pre-existing liver disease may have impaired drug metabolism and abnormal expression of adhesion molecules and procoagulant factors prior to hematopoietic cell transplantation (HCT) [55-57].
The pathophysiology of hepatic SOS shares features with other transplant-related, systemic endothelial diseases (eg, acute graft-versus-host disease, transplant-associated microangiopathy) and drug-associated endothelial cell injury. (See "Pathogenesis of graft-versus-host disease (GVHD)", section on 'Acute GVHD' and "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Therapy-related factors'.)
CLINICAL PRESENTATION — In adults, the peak incidence of presentation with hepatic SOS is 12 days after hematopoietic cell transplantation (HCT); although most adults present within 21 days, up to 40 percent of adults may present >21 days after transplantation [58].
●Clinical – Most patients present with weight gain (≥5 percent) and edema, beginning three to six days after transplantation, followed by firm, painful hepatomegaly with ascites and jaundice [7]. Dyspnea, tachypnea, or other evidence of fluid overload may accompany renal, cardiac, or pulmonary dysfunction in patients with multiorgan dysfunction/failure; some patients with severe SOS also develop encephalopathy or other central nervous system abnormalities.
●Laboratory – Thrombocytopenia that is refractory to platelet transfusions is usually the earliest laboratory abnormality and it may precede clinical findings [7,59]. Most adults have elevated serum aminotransferases and/or alkaline phosphatase, while hyperbilirubinemia (mostly conjugated bilirubin) develops later; in severe disease, increased prothrombin time and other measures of impaired hepatic synthetic function may be present. Kidney function tests are abnormal in approximately half of adults.
EVALUATION — Evaluation of suspected SOS is primarily based on clinical and laboratory findings. Abdominal ultrasound (US) and liver biopsy are important, but not essential, aspects of evaluation and diagnosis.
Clinical evaluation — Every patient who undergoes hematopoietic cell transplantation (HCT) should be evaluated daily with an eye toward features that might suggest development of hepatic SOS. Daily evaluation should include:
●Fluid intake/output and weight.
●Interval history – The patient should be asked about abdominal swelling or pain, nausea/vomiting, dyspnea, peripheral edema, headache.
●Physical examination for peripheral edema and other evidence of fluid accumulation, hepatomegaly, abdominal tenderness and increased girth, bleeding/bruising, and other evidence for organ dysfunction.
Laboratory studies — Laboratory studies should include:
●Daily complete blood count (CBC) and differential count.
●Daily serum chemistries, including electrolytes, renal function tests, and liver function tests (eg, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], total and direct bilirubin, albumin, lactate dehydrogenase [LDH]). Amylase and lipase should be measured, as clinically warranted.
●Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT); fibrinogen and other tests of coagulation, as clinically indicated.
Abdominal ultrasound — Abdominal US is useful for characterizing hepatomegaly, ascites, and/or reversal of portal venous flow, which can be used to evaluate, diagnose, grade severity, and assess response in hepatic SOS. However, there are no pathognomonic findings that definitively distinguish SOS from other conditions in the differential diagnosis.
Findings that are more common in SOS than with other liver disorders in the post-transplant period include ascites, an abnormal portal vein waveform, marked thickening of the gallbladder wall, and a hepatic artery resistance index >0.75 [60]. Reversal of blood flow in the portal vein by Doppler studies has been used to diagnose SOS, but the sensitivity is low [61,62]. One study prospectively determined the prevalence of sonographic hepatobiliary abnormalities in 21 patients undergoing HCT and reported abnormal baseline studies in 62 percent; serial examinations could not discriminate patients with SOS from those without the syndrome [63]. Measurement of liver stiffness by US is being studied, but test characteristics for SOS are not well defined [64-66].
Computed tomography or magnetic resonance angiography may be abnormal in patients with hepatic SOS, but they, too, lack specificity; descriptions of their use are primarily based on case reports [67-69].
Liver biopsy — Liver biopsy and/or measurement of the portal-hepatic venous gradient can be used as diagnostic criteria for hepatic SOS, but there are substantial procedure-related risks. (See 'EBMT diagnostic criteria for adults' below.)
●Transjugular procedure – A transjugular approach (ie, accessing the venous system through the jugular vein) for liver biopsy is safer than a percutaneous biopsy. The transjugular biopsy procedure should be coupled with measurement of the portal-hepatic venous gradient. However, a study that included 60 patients with liver dysfunction who underwent transjugular liver biopsy and measurement of hepatic venous pressure reported bleeding complications in 18 percent, including three procedure-related deaths [70].
●Measurement of the portal-hepatic venous gradient – Measurement of hepatic venous pressures compares the difference between the wedged hepatic venous pressure (which approximates the sinusoidal and portal pressures) and the free hepatic venous pressure. In one study, a hepatic venous pressure gradient >10 mm Hg correlated with the presence of SOS, with 91 percent specificity and 86 percent positive predictive value [70].
●Pathologic findings – Liver sinusoids may be dilated and congested by erythrocytes and nonthrombotic fibrous occlusion of the central veins and small venules; in severe cases, there is widespread zonal liver disruption and centrilobular hemorrhagic necrosis (picture 1) [71-75]. Later pathologic changes include deposition of collagen in the sinusoids, sclerosis of venular walls, fibrosis of venular lumens, and occlusion of terminal hepatic venules and intercalated veins (picture 2).
DIAGNOSIS/DIFFERENTIAL DIAGNOSIS — The diagnosis of hepatic SOS should be considered in any patient who has undergone hematopoietic cell transplantation (HCT) and develops SOS-related symptoms, such as thrombocytopenia refractory to platelet transfusion, hepatomegaly, abdominal pain, ascites, fluid overload, and/or weight gain. There should be a high index of suspicion for this condition, as there is no pathognomonic biomarker, imaging characteristic, or biopsy feature and the presentation varies between individuals.
●Hepatic SOS should be diagnosed using the European Society for Blood and Marrow Transplantation (EBMT) revised diagnostic criteria for adults [75] rather than alternative models (eg, Seattle, Baltimore), because the EBMT model is more sensitive and enables earlier detection compared with the other instruments.
Compared with the Seattle or Baltimore instruments, the EBMT model increases the rate of detection of hepatic SOS and enables earlier diagnosis because it captures anicteric cases, those diagnosed after day 21, and includes alternative modes of diagnosis (eg, ultrasound, liver biopsy). No studies have directly compared the performance of the EBMT versus the Seattle or Baltimore models for adults. However, the Seattle and Baltimore models were compared in a meta-analysis that included nearly 25,000 HCT recipients from 135 studies; the incidence of SOS was 17 percent using the Seattle criteria, but only 10 percent using the more stringent Baltimore criteria [1]. In another retrospective study, 23 percent of 803 patients with SOS (using either the Baltimore criteria, Seattle criteria, or biopsy) had serum bilirubin <2 mg/dL at the time of diagnosis; patients with an anicteric presentation (49 adults and 132 children) would not have been diagnosed using the Baltimore criteria alone [76]. A retrospective registry study reported that among 70 patients who were diagnosed with hepatic SOS according to EBMT criteria, only 24 were diagnosed based on the modified Seattle criteria and 11 met the Baltimore criteria [77].
Our approach to diagnosis and management of hepatic SOS in adults is consistent with recommendations of EBMT and GITMO (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) [75,78].
EBMT diagnostic criteria for adults — Following are the revised EBMT diagnostic criteria for adults; note that these criteria accommodate both classical SOS (ie, <21 days from HCT) and late-onset SOS (ie, ≥21 days after transplantation) [75].
Classical SOS – Diagnosis requires [75]:
●Bilirubin (≥2 mg/dL; ≥34 micromol/L)
plus two of the following:
●Painful hepatomegaly
●Weight gain >5 percent
●Ascites
Late-onset SOS – Diagnosis of late-onset SOS (ie, ≥21 days after transplantation) requires [75]:
●Classical SOS beyond day 21
or
●Histologically-proven SOS
or
●Two or more of the following:
•Bilirubin ≥2 mg/dL
•Painful hepatomegaly
•Weight gain >5 percent
•Ascites
plus
•Hemodynamic or ultrasound evidence of SOS
Other diagnostic models — As discussed above, we suggest use of the revised EBMT criteria for adults, rather than the following models, which are described for purposes of comparison. (See 'Diagnosis/Differential diagnosis' above.)
Seattle — The modified Seattle criteria define hepatic SOS by the otherwise-unexplained occurrence of ≥2 of the following findings within 20 days of HCT; the original Seattle model differed because it used weight gain >2 percent as a criterion [71]:
●Serum bilirubin >2 mg/dL
●Hepatomegaly or right upper quadrant pain
●Sudden weight gain >5 percent of baseline body weight
Baltimore — The Baltimore criteria define hepatic SOS based on [79]:
●Bilirubin >2 mg/dL within 21 days of HCT
plus at least two of the following:
●Hepatomegaly
●Ascites
●Weight gain >5 percent of baseline body weight
Differential diagnosis — The differential diagnosis of SOS includes other causes of liver dysfunction, refractory thrombocytopenia, fluid overload, or multiorgan failure in patients who recently underwent HCT.
●Engraftment syndrome/Capillary leak syndrome/Peri-engraftment respiratory distress syndrome (PERDS) – These syndromes generally occur 9 to 16 days after HCT and are thought to be related to release of proinflammatory cytokines during the period of neutrophil recovery. Each of these conditions can manifest ascites, edema, and weight gain that can resemble hepatic SOS; respiratory distress is a prominent feature of PERDS, which can resemble advanced stage SOS. These syndromes differ from SOS in that they generally manifest noninfectious fever and/or maculopapular rash, while abdominal pain, hepatomegaly, and liver dysfunction are less prominent features. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)
●Acute graft-versus-host disease (aGVHD) – Both SOS and aGVHD can present with abdominal pain and a rising serum bilirubin, but patients with aGVHD usually have concurrent rash and involvement of the gastrointestinal tract. The timing of aGVHD is generally later and coincides with engraftment, but this can overlap the timing of SOS, especially late presentations of SOS. Skin biopsy can distinguish these processes, but liver biopsy should not be performed in children because of excessive bleeding risk. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)
●Abnormal liver function – Numerous conditions cause abnormal liver function tests in the post-transplant period (table 2 and table 3). SOS may also share features of other causes of fulminant hepatic failure including ischemic, viral, malignant/infiltrative, and toxic hepatitis. Some of the most pertinent entities include:
•Hepatic infections – Abnormal liver function tests may be due to viral hepatidities (eg, hepatitis B, hepatitis C), other viruses (eg, cytomegalovirus [CMV], varicella zoster [VZV], Epstein-Barr [EBV], human herpesvirus 6 [HHV-6], adenovirus), and hepatosplenic candidiasis; the likely causes vary with the timing after transplantation. A substantial rise of the transaminases is a hallmark of most such liver infections; in contrast, SOS is typically marked by early refractory thrombocytopenia, followed by a later rise in transaminases or bilirubin. (See "Overview of infections following hematopoietic cell transplantation".)
•Drug toxicity – Many drugs used in the HCT setting, including calcineurin inhibitors (cyclosporine, tacrolimus, sirolimus), methotrexate, azole antifungal agents, trimethoprim-sulfamethoxazole, ribavirin, and busulfan are associated with cholestasis, but they primarily cause hepatocytic damage with elevated transaminases and are not associated with refractory thrombocytopenia that is seen in SOS. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)
●Budd-Chiari syndrome – The acute form of Budd-Chiari syndrome (BCS) can occasionally resemble hepatic SOS. BCS is caused by obstruction of hepatic veins and inferior vena cava, which can be established noninvasively by ultrasonography with Doppler studies, computed tomography scan, or magnetic resonance angiography. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis".)
DISEASE SEVERITY — Grading of hepatic SOS in adults (≥18 years) is based on the revised European Society for Blood and Marrow Transplantation (EBMT) criteria for SOS for adults, which incorporates the time since the first clinical symptoms, bilirubin level and kinetics, transaminases, weight gain, and renal function [75]. We use a simplified version of that score:
●Severe/very severe – Severe/very severe hepatic SOS is characterized by multi-organ dysfunction or ≥2 of the following:
•Time from emergence of first clinical symptoms to diagnosis ≤4 days
•Bilirubin:
-≥5 mg/dL (≥85 micromol/L)
-Doubling <48 hours
•Transaminases >5 times upper limit of normal
•Weight gain >5 percent
•Renal function ≥1.5 times baseline at transplant
●Mild/moderate – Mild or moderate hepatic SOS meets <2 of the above criteria. Moderate disease should be upgraded to severe disease if the patient has ≥2 risk factors [75].
PROPHYLAXIS AND PREVENTION — To reduce the incidence and severity of hepatic SOS and lessen morbidity and mortality, it is important to:
●Mitigate modifiable risk factors, when possible
●Provide prophylaxis
Modifiable risk factors — Risk factors for hepatic SOS should be evaluated prior to hematopoietic cell transplantation (HCT). (See 'Risk factors' above.)
●Pre-existent liver disease/injury should be optimized prior to HCT:
•Medications, supplements, and other substances associated with liver injury should be avoided in the peritransplant period. Examples include azole antifungals, acetaminophen, certain herbal remedies, and excessive alcohol consumption. (See "Drug-induced liver injury" and "Hepatotoxicity due to herbal medications and dietary supplements".)
•Hepatitis C virus should be treated prior to HCT, if possible. (See "Overview of the management of chronic hepatitis C virus infection".)
•When possible, we avoid acute fluid overload in patients undergoing HCT.
•Aggressive iron chelation may reduce the risk for SOS for patients with liver dysfunction caused by iron overload. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)
●Pretransplant/bridging therapy – If possible, we avoid treatment with gemtuzumab ozogamicin or inotuzumab ozogamicin immediately prior to transplantation because they are associated with a substantially increased risk for hepatic SOS. Alternative bridging treatments should be used, when possible.
●Aspects of transplantation – A decision to modify aspects of transplantation to reduce the risk of SOS must be made in the context of management of the underlying disease, comorbid conditions, and institutional approach [80,81]:
•Conditioning regimen – The conditioning regimen contributes importantly to the risk for hepatic SOS, and the following considerations may reduce risk:
-Use of nonmyeloablative conditioning/reduced intensity conditioning, instead of myeloablative conditioning.
-Avoidance of busulfan-based conditioning and total body irradiation (TBI)-containing regimens.
•Graft source – Allogeneic grafts are associated with greater risk than autologous grafts.
●Graft-versus-host disease (GVHD) prophylaxis – When possible, avoidance of higher-risk GVHD prophylaxis regimens, such as:
•Sirolimus plus methotrexate plus tacrolimus
•Methotrexate plus cyclosporine
Some experts also avoid cyclosporine-containing regimens.
Prophylaxis — We provide prophylaxis to all adults undergoing HCT, but some institutions limit prophylaxis to various high-risk patient groups. (See 'Risk factors' above.)
For adults undergoing HCT, we suggest prophylaxis with ursodeoxycholic acid (UDCA) rather than no prophylaxis or prophylaxis using defibrotide or other agents, based on a meta-analysis of four randomized controlled trials that reported reduced incidence of SOS, decreased mortality attributable to SOS, no impact on overall survival (OS), but no increase in adverse effects with UDCA [82].
●UDCA – UDCA is a naturally-occurring hydrophilic bile acid that decreases hepatotoxicity by reducing the hydrophobicity of other naturally-occurring bile acids; UDCA may also decrease secretion of proinflammatory cytokines, thereby minimizing the injury to hepatic sinusoidal endothelial cells [3,54,83].
●Administration and toxicity – We administer UDCA (total daily dose 12 mg/kg or 600 mg orally, divided in two doses) beginning the day before the preparative regimen begins (ie, day –1) and continue treatment for three months. If mucositis or nausea interrupts administration of UDCA, we resume treatment when the patient is again able to take oral medications. UDCA is well-tolerated; the major adverse effects are rash and diarrhea in <5 percent of cases.
●Outcomes – UDCA prophylaxis is associated with a reduced incidence of hepatic SOS and SOS-associated mortality, but there is no clear impact on OS. A Cochrane analysis that included four trials (612 participants) compared UDCA (alone, or with another agent) versus placebo, no treatment, or the same additional agent [82]. Based on low or very low quality of evidence, the analysis reported that UDCA prophylaxis is associated with:
•Reduced incidence of hepatic SOS (risk ratio [RR] 0.60; 95% CI 0.40-0.88)
•Decreased mortality due to hepatic SOS (RR 0.27, 95% CI 0.09-0.87)
•Possible reduction in all-cause mortality (RR 0.70, 95% CI 0.50-0.99)
•No effect on OS (hazard ratio [HR] 0.83, 95% CI 0.59-1.18)
The Cochrane analysis also reported that there was no proven benefit for prophylaxis using other agents (eg, heparin, antithrombin III, PGE1, pentoxifylline) and some are associated with substantial adverse effects (eg, hemorrhage) [82]. Another meta-analysis and systematic review that included 2782 patients enrolled on 12 studies of prophylactic low molecular weight heparin or unfractionated heparin found no reduction in risk of SOS [84].
Prophylaxis with UDCA is recommended by the European Society for Blood and Marrow Transplantation Handbook and the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines [81].
TREATMENT — It is important to have a high index of suspicion for the diagnosis of hepatic SOS and to initiate treatment promptly. Waiting to satisfy all diagnostic criteria will delay the initiation of therapy and increase the risk of progressive organ dysfunction and death. Diagnostic criteria for adults are described above. (See 'EBMT diagnostic criteria for adults' above.)
Treatment is influenced by disease severity, which is assessed as described above. (See 'Disease severity' above.)
Mild/moderate SOS — Patients with mild or moderate severity SOS generally do well with supportive care measures alone, but they must be monitored for progression to severe disease. Defibrotide or other treatments are not well-studied for patients with mild or moderate SOS.
The following supportive measures should be implemented:
●Maintain euvolemia – Daily weights and recording of fluid intake and output are critical to maintaining euvolemia, which is important for adequate renal perfusion, while avoiding restricted pulmonary function due to ascites. Weight gain per se is not a major concern if it does not compromise pulmonary function. Fluid restriction and diuresis should be initiated when intake exceeds output, but it is important to avoid overly aggressive fluid management that can lead to a prerenal failure due to third spacing.
●Minimize hepatotoxic agents – Patients should avoid medications associated with hepatotoxic side effects, including nonsteroidal anti-inflammatory drugs. Pain control may require narcotics to avoid excessive use of acetaminophen.
●Paracentesis – Patients may require serial paracenteses or continuous drainage for ascites that causes discomfort or pulmonary compromise. The amount of fluid removed at each session should be limited to maintain renal perfusion.
For patients who do not improve with supportive care or who develop progressive disease, we treat for severe SOS, as described above. (See 'Severe SOS' below.)
Severe SOS — For patients with severe/very severe hepatic SOS, we suggest prompt treatment with defibrotide, rather than supportive care alone or other treatments. Defibrotide treatment for severe SOS was associated with improved survival, according to a multicenter study of defibrotide treatment versus matched historical control patients [85] and a systematic review of 17 studies [86]. No randomized controlled trials have compared defibrotide with other treatments, but heparin, tissue plasminogen activator, antithrombin III, glucocorticoids, and prostaglandin E1 have no proven efficacy and/or are associated with severe adverse effects (eg, hemorrhage) [8,87-91].
●Defibrotide – Defibrotide is a sodium salt of single-stranded oligodeoxyribonucleotides derived from DNA of porcine intestinal mucosa [92]. Its mechanism of action is not well-understood, but it may involve endothelial protection, restoration of thrombo-fibrinolytic balance, and/or anti-inflammatory properties [93,94].
●Administration – Defibrotide is administered 6.25 mg/kg every 6 hours intravenously for ≥21 days, until SOS resolution or hospital discharge, up to a maximum of 60 days [85]. Defibrotide should be discontinued ≥2 hours prior to invasive procedures and can be resumed once any procedure-related risk of bleeding is resolved. There is no known reversal agent, but the half-life of elimination is <2 hours.
For patients who develop severe SOS while receiving ursodeoxycholic acid (UDCA) prophylaxis, we generally continue UDCA while treating with defibrotide.
Defibrotide is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of severe hepatic SOS.
●Timing – Defibrotide should be started promptly for severe SOS, as early initiation of treatment is associated with improved overall survival (OS) [95,96]. Most studies treated with defibrotide for 14 to 21 days, but the optimal duration of treatment has not been formally defined. In a pooled analysis, more than half of patients who achieved a complete response (CR) required >3 weeks of persistent treatment with defibrotide to achieve CR [97].
●Adverse effects – The most common adverse effects of defibrotide are hypotension, diarrhea, nausea, vomiting, and epistaxis. Hemorrhage and hypersensitivity reactions are reported in <2 percent of patients but can be life-threatening; defibrotide should be discontinued permanently in patients with a severe or life-threatening hypersensitivity reaction.
●Outcomes – Treatment with defibrotide is associated with improved survival in patients with severe/very severe hepatic SOS, compared with supportive care alone. Historically, mortality with severe hepatic SOS was >80 percent [1,98,99].
•A multicenter study of children and adults reported that, compared with 32 historical control patients, 39 patients treated with defibrotide had superior day +100 OS (38 versus 25 percent, respectively) and day +100 CR (26 versus 13 percent) [85]. Treatment was well-tolerated with manageable toxicity; fatal hemorrhagic events were reported in 15 percent of defibrotide-treated patients, compared with 6 percent of controls.
•A systematic analysis of defibrotide treatment included 17 studies (2598 patients) and reported day +100 OS was 54 percent (range 35 to 79 percent) [86]. Other studies of defibrotide for SOS reported similar outcomes and toxicity [95,100].
There are no reports of recurrent SOS in patients who achieve a CR with defibrotide, and most patients who recover from SOS regain normal liver function and do not develop portal hypertension or esophageal varices.
Response to treatment — Clinical findings, laboratory studies, and abdominal ultrasound are used to evaluate the response to treatment, as described above. (See 'Evaluation' above.)
A CR should include improved platelet count and response to platelet transfusions, resolution of coagulopathy, effective diuresis and weight loss, resolution of third spacing of fluids, and resolution of hyperbilirubinemia and hepatomegaly [97].
For patients who do not improve with defibrotide treatment for ≥21 days, we consider treatment for refractory disease, as described below. (See 'Refractory disease' below.)
REFRACTORY DISEASE — No pharmacologic agent has proven benefit for patients with severe hepatic SOS who do not respond adequately to ≥3 weeks of defibrotide treatment. Descriptions of treatment for refractory disease are primarily small, uncontrolled series or case reports.
Options for management of refractory disease include:
●High dose methylprednisolone may be considered for treatment of SOS, but it should be used with caution due to the high risk of infection [81].
●Insertion of a transjugular intrahepatic portosystemic stent-shunt (TIPS) has been performed in small numbers of patients with SOS; some had regression of hepatic and renal symptoms [101-103]. Patients with milder disease are more likely to respond; long-term survival is uncommon but has been reported [103-105]. (See "Overview of transjugular intrahepatic portosystemic shunts (TIPS)".)
●Orthotopic liver transplantation has been successfully performed in small numbers of patients with SOS [106,107]. However, the most patients with severe SOS are not medically fit enough to undergo such a rigorous surgical procedure. In addition, patients at risk for recurrent malignancy are low-priority candidates for liver transplant at many centers. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)
SUMMARY AND RECOMMENDATIONS
●Hepatic sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD), is a life-threatening complication that develops in up to 15 percent of adults who undergo hematopoietic cell transplantation (HCT). A high index of suspicion is required to make the diagnosis, and prompt treatment is needed to reduce the substantial morbidity and mortality associated with SOS.
●Causes – Risk factors for hepatic SOS after HCT include pretransplant patient characteristics (eg, liver disease, age, underlying disease) and transplantation-related factors (eg, conditioning regimen, graft source, graft-versus-host disease [GVHD] prophylaxis regimen) (table 1). Rarely, hepatic SOS can be caused by therapeutic immunoconjugates, radiation therapy, or solid organ transplantation. (See 'Risk factors' above.)
●Clinical presentation – Most patients present within 21 days of HCT with an increased need for platelet transfusions, weight gain, ascites, jaundice, and/or firm, tender hepatomegaly. However, presentations vary and patients may present >21 days after transplantation or without jaundice. Dyspnea, tachypnea, or other evidence of fluid overload may accompany renal, cardiac, or pulmonary dysfunction in patients who progress to multiorgan failure. (See 'Clinical presentation' above.)
●Evaluation – Evaluation of suspected SOS is primarily based on clinical and laboratory findings; abdominal ultrasound and liver biopsy are important, but not essential, aspects of evaluation and diagnosis. (See 'Evaluation' above.)
●Diagnosis and differential diagnosis – The diagnosis of SOS should be considered in any patient who has undergone HCT and develops refractory thrombocytopenia, fluid overload, hepatomegaly, abdominal pain, weight gain, and/or ascites.
•Diagnosis – Hepatic SOS should be diagnosed using the European Society for Blood and Marrow Transplantation (EBMT) revised diagnostic criteria for adults [75], rather than alternative models (eg, Seattle, Baltimore), because it is more sensitive and enables earlier detection compared with the other instruments. EBMT criteria for the diagnosis of classical and late-onset hepatic SOS in adults are presented above. (See 'Diagnosis/Differential diagnosis' above.)
•Differential diagnosis – The differential diagnosis of SOS includes other causes of liver dysfunction, refractory thrombocytopenia, fluid overload, or multiorgan failure in patients who recently underwent HCT, including engraftment syndrome, capillary leak syndrome, peri-engraftment respiratory distress syndrome (PERDS), acute GVHD, and other infectious and chemical causes of liver dysfunction. (See 'Differential diagnosis' above.)
●Prophylaxis and prevention
•Modify risk factors – Risk factors for hepatic SOS should be evaluated prior to HCT, with consideration for modification, when possible. (See 'Modifiable risk factors' above.)
•Prophylaxis – We provide prophylaxis for adults who have at least one major risk factor for hepatic SOS, as described above. Some institutions favor prophylaxis for all adults undergoing HCT. (See 'Prophylaxis' above.)
For prophylaxis against SOS in adults, we suggest ursodeoxycholic acid (UDCA) rather than no treatment or prophylaxis with defibrotide or other agents (Grade 2C), based on reduced incidence of SOS, decreased mortality attributable to SOS, no increase in adverse effects, but no impact on overall survival [82].
●Treatment – We treat SOS according to the severity of disease, determined according to EBMT criteria, as described above (see 'Disease severity' above):
•Mild/moderate – Patients with mild or moderate severity SOS generally do well with supportive care measures, including maintaining euvolemia, avoiding hepatotoxic agents, and paracentesis as needed to relieve abdominal pain. Patients should be monitored for progression to severe/very severe disease.
•Severe/very severe – For patients with severe or very severe hepatic SOS, we suggest treatment with defibrotide, rather than supportive care alone or other approaches (Grade 1C), based on improved survival in a meta-analysis and prospective studies [85,86,95,100].
●Refractory disease – There is no well-defined treatment for severe SOS that does not respond to defibrotide, but high-dose glucocorticoids, transjugular intrahepatic portosystemic stent-shunt (TIPS), and liver transplantation have been used in selected cases.
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