INTRODUCTION — Hepatic sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD), is a systemic endothelial disease that typically presents within the first 30 days after hematopoietic cell transplantation (HCT) with transfusion-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, including cancer chemotherapy and immunotherapy. A high index of suspicion is needed to diagnose 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 children and adults. This topic discusses SOS in children.
Hepatic SOS in adults is discussed separately. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)
EPIDEMIOLOGY — Hepatic SOS, which is also called veno-occlusive disease (VOD), develops in up to one-third of children after hematopoietic cell transplantation (HCT) [1,2], but the incidence varies with the patient population, underlying disease, and aspects of transplantation. Less commonly, hepatic SOS can arise after chemotherapy, immunotherapy, or radiation therapy outside of the setting of HCT.
In an analysis of 135 studies that included nearly 25,000 children and adults who underwent HCT from 1979 to 2007, the mean incidence of SOS was 14 percent; rates in individual studies ranged from 0 to 62 percent, but only a few studies reported rates >40 percent [1]. The incidence overall is declining in recent years but remains approximately twice as high in children as adults, due in part to predisposing diseases and age. In most studies, the incidence in children is 20 to 30 percent, but it can reach as high as 60 percent with certain genetic diseases (eg, hemophagocytic lymphohistiocytosis, osteopetrosis, thalassemia) [2-4]. For children who undergo allogeneic HCT with myeloablative conditioning, the incidence ranges from 10 and 60 percent, but it is lower with reduced-intensity conditioning and ranges from 5 and 30 percent in autologous HCT [5].
Particularly in children, hepatic SOS can occur as a complication of conventional chemotherapy, immunotherapy, or radiation therapy outside of the setting of HCT [5,6]. Chronic treatment with the antimetabolites, thioguanine, azathioprine, or mercaptopurine can also cause SOS, although the presentation is typically subacute or chronic.
Risk factors for hepatic SOS in children are discussed below. (See 'Risk factors' below.)
RISK FACTORS — Risk factors for hepatic SOS after hematopoietic cell transplantation (HCT) include pretransplant patient characteristics (eg, age, underlying disease, liver disease) and transplantation-related factors (eg, conditioning regimen, graft source, graft-versus-host disease [GVHD] prophylaxis regimen) (table 1). The strength of these associations varies between studies [7-9].
Patient characteristics — Infancy is the greatest risk factor for SOS in children undergoing HCT [4]. Pretransplantation characteristics that have been associated with increased risk of hepatic SOS include:
●Age – Children <2 years [4,9,10].
●Underlying disease – Osteopetrosis, hemophagocytic lymphohistiocytosis, juvenile myelomonocytic leukemia, neuroblastoma, and diseases associated with significant liver iron overload and fibrosis (eg, advanced thalassemia) [3,11,12].
●Liver disease – Patients with pre-existent liver disease are at increased risk for hepatic SOS [5,7,8,13-18]. In the largest series, the risk of developing SOS was 3 to 10 times greater in patients with elevated serum aspartate aminotransferase (AST) concentration [7].
Patients with cirrhosis of the liver 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".)
Aspects of transplantation — Transplantation-related factors that have been associated with increased risk for hepatic SOS include:
●Preparative regimen – Certain alkylating agents (eg, busulfan, cytarabine, cyclophosphamide) [4,7,14,19-29]. 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 [15,30-32]. (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) [1,8,33,34]. It is uncertain if there is increased risk associated with HLA-haploidentical donors.
●GVHD prophylaxis – Increased risk has been reported in association with 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 [10,35-37].
Other causes — In children, hepatic SOS can also occur as a complication of conventional chemotherapy, immunotherapy, or radiation therapy outside of the setting of HCT [5]:
●Calicheamicin-linked monoclonal antibodies – Treatment with monoclonal antibodies conjugated with calicheamicin (eg, gemtuzumab ozogamicin, inotuzumab ozogamicin) can cause hepatic SOS and are also associated with increased risk in patients who subsequently undergo HCT [38-41].
●Actinomycin D – Treatment of children with actinomycin D (eg, for treatment for nephroblastoma or sarcomas) is associated with a higher risk for SOS [42,43].
●Conventional radiation therapy and high dose chemotherapy, exposure to pyrrolizidine alkaloids, solid-organ transplantation [2,44,45].
PATHOGENESIS — Hepatic SOS reflects a multifactorial 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 chemotherapy conditioning regimens (eg, busulfan, cyclophosphamide, melphalan), ionizing radiation, or hepatotoxins [44,46]. 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) [47-49].
The pathophysiology of hepatic SOS shares features with other transplant-related, systemic endothelial diseases (eg, engraftment syndrome, 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 — Hepatic SOS in children usually manifests as an increased need for platelet transfusions, followed by fluid overload/weight gain, abdominal complaints, and jaundice, with a peak at 12 days after hematopoietic cell transplantation (HCT). Outside of the setting of HCT, the clinical and laboratory findings of hepatic SOS are similar, but the presentation can be subacute, chronic, or it can follow fulminant liver failure.
●Typical presentation – Most children present within 21 days of HCT with thrombocytopenia refractory to platelet transfusions, unexplained weight gain, ascites, and/or firm, tender hepatomegaly (even recognizing that abdominal pain can be difficult to assess in infants and toddlers), and jaundice [50]. Refractory or consumptive thrombocytopenia is often the earliest manifestation of SOS. Dyspnea, tachypnea, or other evidence of fluid overload may accompany renal, cardiac, or pulmonary dysfunction in children who progress to multiorgan dysfunction/failure.
●Late or anicteric presentation – Importantly, one-fifth of children present with hepatic SOS >21 days after HCT, and nearly one-third are not icteric [2,50,51].
The clinical presentation of hepatic SOS that follows chemotherapy, immunotherapy, or radiation therapy outside of the setting of HCT is more likely to be subacute or chronic, but it can also arise after fulminant liver failure in the company of acute hepatic necrosis [6].
EVALUATION — Evaluation of suspected SOS is based on clinical and laboratory findings, which are supplemented by abdominal ultrasound (US). A high index of suspicion for the condition is required. In settings outside the context of hematopoietic cell transplantation (HCT), the child may not be available for daily evaluation and there can be even greater reliance on imaging.
Clinical evaluation — Every child who undergoes HCT requires daily clinical evaluation with an eye toward features that might suggest development of hepatic SOS. Daily evaluation should include:
●Fluid intake and output and weight.
●Interval history – The child should be asked about abdominal swelling or pain (especially in the right upper quadrant or epigastrium), nausea/vomiting, dyspnea, peripheral edema, headache.
●Physical examination should include daily girth and other evidence of fluid accumulation, hepatomegaly, and abdominal tenderness.
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 — Children should have an abdominal US prior to HCT to establish a baseline image. For children suspected of having SOS, comparison to the baseline study is important for making the diagnosis of hepatic SOS, grading disease severity, and assessing treatment response.
Serial US can be used to detect changes in liver size and/or presence of ascites. The baseline abdominal US is important because many pediatric patients come into transplant with pre-existing hepatomegaly and/or ascites, and abnormalities associated with SOS may be difficult to distinguish from those related to the underlying disease or other transplant-associated complications. Findings consistent with hepatic SOS include ascites, hepatomegaly, gallbladder changes, reversal of portal vein blood flow, decreased size of hepatic veins; and/or elevated hepatic arterial resistive indices [50].
Computed tomography or magnetic resonance imaging can substitute for or complement US, but these techniques are less desirable because they expose the child to radiation and/or require sedation for younger patients.
Liver biopsy — Liver biopsies should generally not be performed in children because of the high risk of complications. Furthermore, by the time that a biopsy would reveal the diagnosis of SOS, the child would likely have severe disease. A single-institution study of 16 children who underwent liver biopsies reported hemorrhage or other complications after five of the procedures [52].
DIAGNOSIS AND SEVERITY
Diagnosis — The diagnosis of hepatic SOS should be considered in any child who has undergone hematopoietic cell transplantation (HCT) and develops SOS-related findings, such as refractory thrombocytopenia, hepatomegaly, abdominal pain, ascites, fluid overload, and/or weight gain. The diagnosis may also be suspected in children who receive chemotherapy, immunotherapy, or radiation therapy who have clinical, laboratory, or imaging findings consistent with otherwise-unexplained chronic, subacute, or fulminant liver disease. It is important to have a high index of suspicion for the diagnosis of hepatic SOS, as the clinical presentation varies between patients and there is no pathognomonic diagnostic biomarker, imaging characteristic, or biopsy feature.
The European Society for Blood and Marrow Transplantation (EBMT) revised diagnostic criteria for children should be used for diagnosis [2], because it is more sensitive and enables earlier diagnosis than older diagnostic instruments (eg, Seattle and Baltimore models). The Seattle and Baltimore models should not be used in children because they do not adequately account for late and anicteric presentations of SOS, do not include refractory thrombocytopenia as a diagnostic criterion, and do not account for the prevalence of pre-existent hepatomegaly/hyperbilirubinemia in many children undergoing HCT. (See 'Clinical presentation' above.)
Diagnosis of hepatic SOS in children using the EBMT model is based on ≥2 of the following [2]:
●Unexplained transfusion-refractory or consumptive thrombocytopenia (eg, need for platelet transfusions at least once daily)
●Otherwise unexplained weight gain on three consecutive days despite the use of diuretics, or a weight gain >5 percent above baseline value
●Hepatomegaly (best if confirmed by imaging) above baseline value
●Ascites (best if confirmed by imaging) above baseline value
●Rising bilirubin from a baseline value on three consecutive days or bilirubin ≥2 mg/dL within 72 hours
We generally advise against performing a liver biopsy for diagnosis in children because the procedure is associated with substantial risks in this setting and because treatment should be initiated when the first evidence of hepatic SOS is detected, at which time the liver biopsy may not yet be revealing.
The EBMT model provides greater sensitivity and enables earlier diagnosis in children than the Seattle and Baltimore models. A single-center retrospective study of pediatric and adolescent/young adult patients who underwent HCT reported that application of the EBMT criteria was associated with a higher incidence (16 percent) and earlier diagnosis (by approximately three days), compared with the incidence using the modified Seattle (12 percent) and Baltimore (7 percent) criteria [53]. Importantly, at the time of diagnosis, refractory thrombocytopenia was present in three-quarters of children and nearly two-thirds were anicteric (although nearly all children later developed hyperbilirubinemia, over a median of four days). Another retrospective study reported an anicteric presentation of SOS in nearly one-third of children, which would not have been captured using the Seattle and Baltimore models [54].
Our approach to diagnosis and management of hepatic SOS in children is consistent with recommendations of EBMT and GITMO (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) [2,55]. The Seattle and Baltimore models are described separately. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Other diagnostic models'.)
Severity grading — The EBMT has created a grading system based on clinical status, laboratory findings, and imaging that can distinguish between children with mild/moderate disease versus severe/very severe disease [2]. Severity grading is helpful for assessing the duration of treatment of SOS and for retrospective assessment of outcomes after HCT.
EBMT criteria for severity grading in children (<18 years) include clinical features (eg, ascites, oxygen requirement, cognitive impairment), severity and kinetics of laboratory abnormalities (eg, persistent thrombocytopenia, transaminases, bilirubin, kidney function, coagulation), and can include imaging [2]:
●Severe/very severe – Severe/very severe hepatic SOS is characterized by the presence of any of the following [2]:
•Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], glutamate dehydrogenase [GLDH]): >5 times upper limit of normal
•Refractory thrombocytopenia for >7 days
•Bilirubin:
-≥2 mg/dL (≥34 micromol/L)
-Doubling ≤48 hours
•Ascites requiring paracentesis/external drainage
•Impaired coagulation
•Renal function (glomerular filtration rate [GFR]): <30 mL/min
•Oxygen requirement that necessitates invasive pulmonary ventilation (including continuous positive airway pressure [CPAP])
•New onset of cognitive impairment
●Mild/moderate – Mild or moderate hepatic SOS meets none of the above criteria for severe/very severe disease.
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 hematopoietic cell transplantation (HCT).
For patients who underwent HCT, the differential diagnosis includes:
●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 be manifest with ascites, edema, and weight gain that resembles hepatic SOS; respiratory distress is a prominent feature of PERDS, which can resemble advanced stage SOS. These syndromes differ from SOS in that they are generally associated with noninfectious fever and/or maculopapular rash, while abdominal pain, hepatomegaly, and liver dysfunction are less prominent features than in SOS. (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 in late onset SOS. Skin biopsy can distinguish these processes, but liver biopsy should not be performed in children suspected to have SOS because of excessive bleeding risk. Diagnosis of aGVHD is discussed separately. (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".)
Outside of the context of HCT, other causes of acute or chronic liver failure, such as hemophagocytic lymphohistiocytosis (HLH), viral hepatitis, hepatotoxins, inherited metabolic diseases, hypoperfusion, and immune dysregulation should be considered, as discussed separately. (See "Acute liver failure in children: Etiology and evaluation".)
PREVENTION — To reduce the incidence and severity and lessen the morbidity and mortality associated with hepatic SOS, it is important to:
●Mitigate risk factors, when possible.
●Implement prophylaxis for selected patients.
Modifiable risk factors — Risk factors for hepatic SOS should be reviewed before proceeding to hematopoietic cell transplantation (HCT). (See 'Risk factors' above.)
Certain risk factors for hepatic SOS can be modified, while others (eg, age, the underlying disease) cannot be altered, but may influence decisions regarding prophylaxis or the choice of therapies prior to HCT. (See 'Prophylaxis' below.)
●Pre-existent liver disease/injury should be optimized prior to HCT:
•Medications and supplements associated with liver injury should be avoided in the peritransplant period. Examples include azole antifungal agents and acetaminophen. (See "Drug-induced liver injury".)
•Aggressive iron chelation may reduce the risk for SOS for patients with liver dysfunction caused by iron overload (eg, advanced thalassemia, chronic transfusions for aplastic anemia or myelodysplastic syndromes). However, a decision to pursue months of chelation therapy to reduce iron load prior to HCT must be individualized and balance the risks of the underlying condition versus the potential for hepatic SOS. (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; we generally treat with an alternative bridging therapy or wait four to six weeks between exposure and the start of HCT conditioning.
●Aspects of transplantation – A decision to modify aspects of transplantation that can reduce risk must be made in the context of the preferred techniques for the underlying disease, comorbid conditions, and institutional approach [45,56]:
•Conditioning regimen – The following considerations may be beneficial for reducing the risk for hepatic SOS:
-Use of nonmyeloablative conditioning/reduced intensity conditioning, instead of myeloablative conditioning.
-Avoidance of busulfan-based and total body irradiation (TBI)-containing conditioning regimens.
-If a busulfan-containing regimen is chosen, administration of busulfan prior to cyclophosphamide (rather than the reverse order) and targeted dosing of busulfan is preferred [1].
●GVHD prophylaxis – When possible, we avoid higher-risk graft-versus-host disease (GVHD) prophylaxis regimens, such as:
•Sirolimus plus methotrexate plus tacrolimus
•Methotrexate plus cyclosporine
Some experts also avoid cyclosporine-containing regimens, but continuous infusion of cyclosporine (to avoid peak levels) may mitigate endothelial damage.
Prophylaxis
Selection of patients — Selection of patients for prophylaxis varies by institution; some centers administer prophylaxis to all children undergoing HCT, while others limit prophylaxis to various high-risk patient groups.
We provide prophylaxis based on the presence of at least one major risk factor for hepatic SOS:
●Children <2 years
●Pre-existing liver disease
●Recent treatment with gemtuzumab ozogamicin or inotuzumab ozogamicin
●Second myeloablative HCT
●Disease:
•High-risk neuroblastoma undergoing autologous HCT
•Hemophagocytic lymphohistiocytosis (HLH)
•Iron overload (eg, high liver iron content and/or bridging fibrosis) due to thalassemia or chronic transfusion therapy
Choice of agent — For children at high-risk for hepatic SOS (described above), we suggest prophylaxis with defibrotide, rather than with ursodeoxycholic acid (UDCA) or other agents (eg, heparin, fresh frozen plasma, anti-thrombin III); some experts consider UDCA an acceptable option for prophylaxis in children.
Defibrotide is associated with reductions of incidence, severity, and mortality attributable to SOS and modest toxicity, but no improvement in overall survival (OS), based on two meta-analyses [57,58] and a phase 3 trial [59]. Although UDCA prophylaxis is also associated with favorable outcomes, the data primarily reflect treatment in adults rather than children [58,60-62]. A Cochrane review found insufficient evidence to support the use of other agents for prophylaxis of SOS [58].
Neither defibrotide nor UDCA is approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for prophylaxis of hepatic SOS. Administration and outcomes with these agents are described below. (See 'Defibrotide prophylaxis' below and 'Ursodeoxycholic acid prophylaxis' below.)
Administration and outcomes with defibrotide and UDCA are described below. (See 'Defibrotide prophylaxis' below and 'Ursodeoxycholic acid prophylaxis' below.)
Defibrotide prophylaxis — Defibrotide is a mixture of single-stranded oligodeoxyribonucleotides derived from porcine intestinal mucosa [63].
●Administration – Defibrotide is generally administered as 6.25 mg/kg every 6 hours intravenously and continued for ≥21 days post-transplant or until resolution of clinical findings, if hepatic SOS develops. Toxicity is modest, but non-fatal bleeding has been reported.
●Outcomes – A systematic analysis of defibrotide prophylaxis that included 1230 patients from 13 studies reported defibrotide prophylaxis was associated with a lower incidence of SOS (relative risk [RR] 0.47; 95% CI 0.31-0.73) and reduced severity of disease, but no effect on OS [57]. For children at high risk of developing SOS, a phase 3 trial reported that defibrotide prophylaxis reduced the incidence of hepatic SOS 30 days post-HCT (12 versus 20 percent, respectively), did not affect OS, but was associated with an increased risk of bleeding [59]. Single-center studies have also suggested that defibrotide might offer benefit for prevention of hepatic SOS in children [64,65].
Ursodeoxycholic acid prophylaxis — UDCA is a naturally-occurring hydrophilic bile acid that is used for SOS prophylaxis in adults and has some evidence of efficacy in children.
●Administration – UDCA prophylaxis (total daily dose 12 mg/kg or 600 mg, divided in two doses) should begin the day before the preparative regimen begins (ie, day –1) and continue for three months. UDCA is well-tolerated, and diarrhea or rash are the major adverse effects (<5 percent of cases). Mucositis and nausea in the early post-transplant period may temporarily interrupt administration; when this occurs, we resume treatment when the patient is again able to take oral medications.
●Outcomes – UDCA prophylaxis has not been persuasively demonstrated to be effective in children. In studies that primarily included adults, UDCA prophylaxis was associated with a reduced incidence of hepatic SOS and SOS-associated mortality and no clear impact on OS. A meta-analysis included four trials (612 participants) that compared UDCA (with or without additional treatment) versus placebo, no treatment, or the same additional treatment [58]. Based on low or very low quality of evidence, this analysis concluded that UDCA was associated with reduced incidence of hepatic SOS (RR 0.60; 95% CI 0.40-0.88), possible reduction in all-cause mortality (RR 0.70, 95% CI 0.50-0.99), and mortality due to hepatic SOS (RR 0.27, 95% CI 0.09-0.87), and no effect on OS (hazard ratio [HR] 0.83, 95% CI 0.59-1.18).
TREATMENT — Vigilance and a high level of suspicion are needed to diagnose hepatic SOS and promptly initiate therapy. (See 'Diagnosis' above.)
Importantly, treatment should begin with the first evidence of SOS, rather than waiting for development of severe disease, as described below. (See 'Not currently receiving defibrotide' below.)
Choice of treatment — The choice of treatment is influenced by whether the patient is already receiving defibrotide prophylaxis.
Not currently receiving defibrotide — For patients with hepatic SOS who are not currently receiving defibrotide prophylaxis, we suggest treatment with defibrotide, rather than other treatments or supportive care alone. Defibrotide is associated with improved survival and acceptable toxicity in SOS, based on prospective and retrospective studies [66-69]. No phase 3 trials have compared defibrotide with other treatments, but other agents (eg, heparin, tissue plasminogen activator, antithrombin III, glucocorticoids, prostaglandin E1) are associated with severe adverse effects (eg, hemorrhage) and no proven efficacy [5,10,70].
●Administration of defibrotide – Defibrotide is generally administered as 6.25 mg/kg every 6 hours intravenously and continued for ≥21 days or until resolution of clinical and laboratory abnormalities, as described below. Defibrotide should be discontinued at least two 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 SOS while receiving ursodeoxycholic acid (UDCA) prophylaxis, we stop UDCA while treating with defibrotide.
Defibrotide is approved for treatment of severe hepatic SOS by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
●Adverse effects – The most common adverse effects of defibrotide are hypotension, diarrhea, nausea, vomiting, and epistaxis; hemorrhage and hypersensitivity reactions are less common but can be life-threatening. Hypersensitivity reactions occurred in <2 percent of patients treated with defibrotide; it should be discontinued permanently in patients with a severe or life-threatening hypersensitivity reaction.
●When to initiate treatment – Treatment for SOS in children should begin with the first evidence of SOS, rather than waiting for development of severe disease. Early initiation of defibrotide is associated with better outcomes and improved overall survival (OS) [66,71]. It is estimated that 30 to 60 percent of children will progress to multiorgan dysfunction/failure (MOD/MOF) [1,46,59,69], so waiting to satisfy all diagnostic criteria for SOS delays the initiation of therapy and greatly increases the risk of progressive MOD/MOF and death.
●Duration of treatment – We generally treat with defibrotide for ≥21 days or until resolution of clinical and laboratory abnormalities (eg, platelet refractoriness, resolution of coagulopathy, effective diuresis and weight loss, resolution of third spacing of fluids, hyperbilirubinemia, and hepatomegaly), as described above. (See 'Evaluation' above.)
●Outcomes – Treatment with defibrotide is associated with improved survival in patients with severe/very severe hepatic SOS, compared with supportive care alone. A systematic analysis of defibrotide treatment included 17 studies (representing 2598 patients) and reported day +100 OS was 54 percent (range 35 to 79 percent) [68]. By contrast, severe SOS was previously associated with >80 percent mortality [1,72,73].
Studies of defibrotide for severe SOS in children include:
•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 complete response (CR; 26 versus 13 percent) [69]. Treatment was well-tolerated with manageable toxicity; fatal hemorrhagic events were reported in 15 percent of treated patients, compared with 6 percent of controls.
•A multicenter retrospective study that included 22 children and adolescents with severe disease reported 50 percent CR, 36 percent day +100 OS, and none of the long-term survivors died with SOS-related causes [66].
There are no reports of recurrent SOS in patients who achieve a CR to defibrotide, and most patients who recover from SOS regain normal liver function and do not develop sequelae, such as portal hypertension or esophageal varices.
Currently receiving defibrotide — No pharmacologic agent has proven benefit for patients with severe hepatic SOS who do not respond adequately to defibrotide (ie, as prophylaxis or treatment). We generally continue defibrotide beyond 21 days for children who are only slowly or incompletely responding to treatment. Options for management of refractory disease include:
●High dose glucocorticoid – High dose methylprednisolone may be considered for treatment of SOS, but it should be used with caution due to the increased risk of infection [74].
●Transjugular intrahepatic portosystemic stent-shunt (TIPS) – Insertion of a TIPS has been performed in small numbers of patients with SOS; some patients had regression of the hepatic and renal symptoms [75-77]. Patients with milder disease may be more likely to respond; long-term survival appears to be uncommon but has been reported [77-79]. (See "Overview of transjugular intrahepatic portosystemic shunts (TIPS)".)
●Liver transplantation – Orthotopic liver transplantation has been successfully performed in small numbers of patients with SOS [80,81]. 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".)
Supportive care — All patients should receive supportive care to mitigate hepatic SOS, with attention to fluid balance, maintaining intravascular volume and renal perfusion, and limiting third space fluid collection. The following supportive measures should be considered:
●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. Fluid restriction and diuresis should be initiated when intake greatly exceeds output, but it is important to avoid overly aggressive fluid management that can lead to prerenal failure due to third spacing.
●Minimize hepatotoxic agents – Medications that are associated with liver injury should be avoided. Pain control may require narcotics to avoid excessive use of acetaminophen.
●Paracentesis – Patients may require serial paracentesis or continuous drainage for ascites that causes discomfort or pulmonary compromise. For children, relief of pulmonary compromise is important to avoid assisted ventilation. The amount of fluid removed at each session should be limited to maintain renal perfusion. Decreasing ascitic loss may be an indication of response to treatment.
SUMMARY AND RECOMMENDATIONS
●Hepatic sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD), is a life-threatening complication that develops in up to 30 percent of children who undergo hematopoietic cell transplantation (HCT). Rarely, SOS can arise after other causes of liver injury, including cancer chemotherapy and immunotherapy. Hepatic SOS typically presents with refractory thrombocytopenia, abdominal pain, hepatomegaly, ascites, jaundice, and/or multi-organ failure in the days or weeks after HCT.
●Causes – Risk factors for hepatic SOS after HCT include pretransplant patient characteristics (eg, age, underlying disease, liver disease) and transplantation-related factors (eg, conditioning regimen, graft source, graft-versus-host disease [GVHD] prophylaxis regimen) (table 1). Hepatic SOS can also be caused by chemotherapy, therapeutic immunoconjugates, radiation therapy, or solid organ transplantation in the absence of HCT. (See 'Risk factors' above.)
●Clinical presentation – Most children present within 21 days of HCT with an increased need for platelet transfusions, unexplained weight gain, ascites, jaundice, and/or firm, tender hepatomegaly. However, presentations vary between individuals and a significant percentage of children present >30 days after transplantation or without jaundice. Dyspnea, tachypnea, or other evidence of fluid overload may accompany renal, cardiac, or pulmonary dysfunction in children who progress to multi-organ failure (MOF). (See 'Clinical presentation' above.)
●Evaluation – Evaluation of suspected SOS is based on clinical and laboratory findings, which are supplemented by abdominal ultrasound. All children should have an abdominal ultrasound prior to HCT to establish a baseline image. (See 'Evaluation' above.)
●Diagnosis – The diagnosis of SOS should be considered in any child who has undergone HCT and develops thrombocytopenia refractory to platelet transfusion, fluid overload, hepatomegaly, abdominal pain, weight gain, and/or ascites. Hepatic SOS is a clinical diagnosis. It is important to have a high index of suspicion, as the clinical presentation varies between individuals and there is no pathognomonic diagnostic biomarker, imaging characteristic, or biopsy feature.
The European Bone Marrow Transplantation (EBMT) revised criteria for children [2] should be used to diagnose hepatic SOS, rather than alternative models (eg, Seattle or Baltimore models), which are ill-suited for children because they do not account for the late and anicteric presentations in children. (See 'Diagnosis and severity' above.)
●Differential diagnosis – The differential diagnosis of SOS includes other causes of liver dysfunction, refractory thrombocytopenia, fluid overload, or MOF 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.
●Prevention – To reduce the incidence and severity of hepatic SOS, it is important to:
•Mitigate risk factors. (See 'Modifiable risk factors' above.)
•Implement prophylaxis for selected patients.
-We provide prophylaxis based on the presence of at least one major risk factor, but some institutions administer prophylaxis to all children undergoing HCT. (See 'Selection of patients' above.)
-For children at high risk for hepatic SOS (described above), we suggest prophylaxis with defibrotide, rather than ursodeoxycholic acid (UDCA) or other agents (Grade 2B); some experts consider UDCA an acceptable option for prophylaxis in children.
Defibrotide is associated with reductions of incidence, severity, and mortality attributable to SOS and modest toxicity, but no improvement in overall survival (OS), based on two meta-analyses [57,58] and a phase 3 trial [59]. UDCA prophylaxis has not been persuasively demonstrated in children and there is insufficient evidence to support the use of other agents for prophylaxis of SOS [58].
●Treatment – The choice of treatment for hepatic SOS is influenced by whether the patient is already receiving defibrotide prophylaxis:
•Patients not currently receiving defibrotide – For patients with hepatic SOS who are not currently receiving defibrotide prophylaxis, we suggest treatment with defibrotide, rather than other treatments or supportive care alone. Defibrotide is associated with improved survival and acceptable toxicity in SOS, based on prospective and retrospective studies [66-69]. No phase 3 trials have compared defibrotide with other approaches (eg, heparin, tissue plasminogen activator, and antithrombin III), but no other treatment has proven efficacy for SOS. (See 'Not currently receiving defibrotide' above.)
Treatment should begin with the first evidence of SOS, rather than waiting for development of severe disease, and continue for at least three weeks or until there is resolution of findings related to SOS.
•Patients receiving defibrotide – For patients who develop SOS while receiving defibrotide prophylaxis or who do not respond adequately to ≥3 weeks of defibrotide treatment we continue treatment with defibrotide, as some patients will have a delayed response. There are limited alternative therapeutic options, such as high dose glucocorticoids or transjugular intrahepatic portosystemic stent-shunt (TIPS). (See 'Currently receiving defibrotide' above.)
