Introduction
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a serious complication that can occur after high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). Less commonly, it can also arise from toxic alkaloid ingestion, high doses of radiotherapy, or liver transplantation. Clinically, VOD/SOS is characterized by hepatomegaly, right-upper quadrant pain, jaundice, and ascites. However, it’s important to note that anicteric forms, where jaundice is absent, can occur, especially in children. The severity of VOD/SOS can be further compounded by multiorgan disease (MOD), affecting the lungs, kidneys, and central nervous system, which significantly increases mortality rates, often exceeding 80%. MOD is a critical predictor of severe VOD/SOS.
In HSCT patients, the underlying cause of VOD/SOS is endothelial cell injury. This injury leads to the breakdown of the sinusoidal wall, endothelial cell detachment, and subsequent sinusoidal obstruction. This obstruction results in postsinusoidal portal hypertension (PH), driving the clinical manifestations of the syndrome. The incidence of post-transplant VOD/SOS varies widely, from around 5% to as high as 60% in pediatric high-risk populations, depending on transplant settings and study methodologies.
The occurrence of VOD/SOS significantly impacts transplant outcomes, with mortality rates reaching up to 80% in severe cases in older studies. More recent research, particularly in patients treated with defibrotide, suggests improved survival rates. Early diagnosis and prompt treatment are crucial for improving patient survival. Management strategies include supportive care, intensive treatment, and specific drug therapy. This review will focus on the advances and challenges in the Vod Diagnosis of hepatic veno-occlusive disease, particularly in the context of HSCT.
Pathophysiology of VOD/SOS
The pathogenesis of VOD/SOS begins with damage to the sinusoidal endothelium in the liver (Figure 1). This endothelial injury disrupts cell junctions, creating gaps in the endothelial barrier. Red blood cells leak through these gaps and accumulate in the Disse space. This process leads to the detachment of endothelial cells, which can then embolize into the centrilobular vein, causing postsinusoidal obstruction.
Figure 1: Physiopathology of VOD/SOS. This diagram illustrates the complex mechanisms involved in the development of VOD/SOS, including endothelial damage, inflammation, and coagulation pathways. Understanding these pathways is crucial for effective diagnosis and targeted therapies. G-CSF, granulocyte colony-stimulating factor; PAI, plasminogen activator inhibitor-1; TF, tissue factor; tPA, tissue plasminogen activator; MMP-9, matrix metallopeptidase 9.
Several factors contribute to this initial endothelial damage. Conditioning regimens used in HSCT are a major culprit, with higher plasma levels of cytotoxic drugs like busulfan increasing VOD/SOS risk. Cytokines released from injured tissues, endogenous microbial products, transplant-related drugs like granulocyte colony-stimulating factor (G-CSF) and calcineurin inhibitors, and the engraftment process itself also play roles. Centrilobular regions of the liver are particularly vulnerable due to lower levels of glutathione (GSH), making them more susceptible to toxic damage from chemotherapy drugs metabolized by the cytochrome P450 complex. Genetic factors, such as a GSH S-transferase M1 null genotype, can further reduce detoxification capacity and increase VOD/SOS susceptibility. The immature enzymatic systems in children may also contribute to the higher incidence of VOD/SOS in this population.
Emerging evidence suggests that alloreactivity may also contribute to VOD/SOS. The higher incidence after allogeneic HSCT compared to autologous HSCT, and in mismatched unrelated donor transplants, points towards a role for alloreactive T cells targeting endothelial cells.
Post-HSCT, endothelial cells exhibit a procoagulant and proinflammatory state, evidenced by increased levels of circulating markers of endothelial activation, such as procoagulant factors, adhesion molecules, circulating endothelial cells, endothelial progenitor cells, and microparticles. Nitric oxide deficiency, potentially caused by postconditioning toxicity, appears to be linked to endothelial cell detachment. This deficiency promotes the production of matrix metalloproteinase 9 (MMP-9), which is strongly implicated in VOD/SOS development, likely by facilitating endothelial cell detachment. Inhibition of MMPs in vivo has been shown to prevent VOD/SOS occurrence in experimental models.
In addition to endothelial cell embolization, the proliferation of perisinusoidal stellate cells and subendothelial fibroblasts, along with extracellular matrix deposition in the terminal hepatic vein, further contributes to blood flow obstruction. This leads to perivenular fibrosis spreading into the liver parenchyma, blocking liver blood outflow, causing hepatic congestion, and ultimately leading to postsinusoidal PH. Given the central role of endothelial injury, VOD/SOS is now classified as a transplant-related endothelial dysfunction syndrome.
Clinical Presentation and Evolving Diagnostic Criteria for VOD Diagnosis
The clinical presentation of VOD/SOS is a direct consequence of portal hypertension. Key features include rapid weight gain due to fluid retention, often unresponsive to diuretics, hyperbilirubinemia, painful hepatomegaly, and ascites. Traditionally, VOD/SOS manifests within 21 days post-transplant. However, late-onset VOD/SOS is now recognized as a distinct entity, defined by the European Society for Blood and Marrow Transplantation (EBMT). Late VOD/SOS is reported in a significant proportion of patients, occurring in up to 39.3% of adults and 16.7% of children.
Table 1 summarizes the modified Seattle, Baltimore, and EBMT diagnostic criteria for adults and children, highlighting the evolution of vod diagnosis approaches.
Table 1.
Modified seattle, Baltimore, and EBMT diagnostic criteria in adults (A) and in children (B).
| (A) ADULTS |
|---|
| Modified Seattle criteriaa |
| Presentation within 20 d from HSCT of ≥2 of the following: – Bilirubin >2 mg/dL – Hepatomegaly, right-upper quadrant pain – Weight gain >2% over baseline due to fluid retention |
| (B) CHILDREN |
| No time onset limitation for SOS/VOD occurrence |
| The presence of ≥2 of the following paramethersb: • Unexplained refractoriness to platelets transfusions defined as ≥1 weight-adjusted platelet substitution/day to maintain institutional transfusion guidelines.c • Otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or a weight gain >5% above baseline value • Hepatomegaly (best if confirmed by imaging such as US, CT or MRI) above baseline value measured pre-HSCT • Ascites (best if confirmed by imaging such as US, CT or MRI) above baseline value measured pre-HSCT • Increase of bilirubin above baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 h |
aThese symptoms/signs should not be attributable to other causes.
bWith the exclusion of other potential differential diagnoses.
cOne or more weight-adjusted platelet substitution/day to maintain institutional transfusion guidelines.
CT, computed tomography; HSCT, hematopoietic stem cell transplantation; MRI, magnetic resonance imaging; US, ultrasonography.
VOD/SOS can manifest with varying degrees of severity, from mild, self-resolving forms to severe forms with organ damage and MOD. Given the high mortality associated with severe VOD/SOS, particularly when complicated by MOD, vigilant daily monitoring for early signs and symptoms is essential. While still life-threatening, advancements in management have improved outcomes compared to historical data.
Traditionally, vod diagnosis relied on the Baltimore or modified Seattle criteria, based on clinical findings and exclusion of other diagnoses. However, differential diagnosis can be challenging, as conditions like fluid overload, constrictive pericarditis, drug-induced liver injury (DILI), cholangitis lenta, sepsis, and hepatic graft-versus-host disease (GvHD) can mimic VOD/SOS. A key difference between Baltimore and Seattle criteria is the mandatory hyperbilirubinemia in the Baltimore criteria, potentially delaying diagnosis in milder or anicteric cases. Anicteric VOD/SOS is more common in children, occurring in up to 30% of cases, compared to 12% in adults.
Recognizing these limitations, the EBMT developed new diagnostic criteria for both adults and children, along with severity grading scales. The EBMT criteria for adults distinguish between classical VOD/SOS (within 21 days post-HSCT) and late-onset VOD/SOS (beyond 21 days). Late-onset VOD/SOS can be diagnosed based on classical criteria, histological evidence, or a combination of clinical criteria and ultrasound or hemodynamic evidence. In children, the EBMT criteria are not time-dependent and include criteria such as unexplained refractory thrombocytopenia, unexplained weight gain, hepatomegaly, ascites, and bilirubin elevation. The inclusion of refractory thrombocytopenia and the de-emphasis on bilirubin as a mandatory criterion reflect the pediatric specificities of vod diagnosis.
The EBMT severity grading scales, presented in Table 2, consider the dynamic changes in hepatic and renal function tests to assess disease severity and guide early treatment initiation.
Table 2.
EBMT criteria for severity grading of suspected VOD in adults (A) and in children (B).
| Mild | Moderate | Severe | Very severe |
|---|---|---|---|
| (A) ADULTS | |||
| Time since first symptoms | >7 d | 5–7 d | ≤ 4 d |
| Bilirubin (mg/dL) | ≥2 to | ≥3 to | ≥5 to |
| Kinetics of bilirubin increase | Doubling in 48 h | ||
| AST, ALT ( × UNV) | ≤ 2 | >2 to ≤ 5 | >5 to ≤ 8 |
| Weight gain (%) | ≥5 to | ≥5 to | ≥10 |
| Creatinine ( × baseline pre-HSCT) | ≥1.2 to | ≥1.5 to | ≥2 or other data of MOD |
| (B) CHILDREN | |||
| Liver function tests (AST, ALT, GLDH)a | ≤ 2 × | >2 and ≤ 5 × | >5 × |
| Persistent platlets refractorinessa | 3–7 d | >7 d | |
| Bilirubin (mg/dL)a, b | >2 | ||
| Ascitesa | Minimal | Moderate | Need of paracentesis |
| Kinetics of bilirubin increase | Doubling within 48h | ||
| Coagulation | Normal | Impaired | Impaired coagulation with need of replacement of coagulation factors |
| Renal function GFR (mL/min) | 89–60 | 59–30 | 29–15 |
| Pulmonary function (oxygen requirement) | >2 L/min | Invasive pulmonary ventilation (including CPAP) | |
| CNS impairment | Absent | New onset cognitive impairment |
Patients belong to the category that fulfills ≥2 criteria. If patients fulfill ≥2 criteria in two different categories, they should be classified in the most severe category, in the presence of two or more risk factors for SOS, patients should be in the upper grade.
aPresence of two or more of these criteria qualifies for an upgrade to CTCAE level 4 (very severe SOS/VOD).
bExcluding preexistent hyperbilirubinemia due to primary disease.
ALT, alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CPAP, continuous positive airway pressure; CTCAE, Common Terminology Criteria for Adverse Events; GFR, glomerular filtration rate; GLDH, glutamate dehydrogenase; MOD, multi-organ dysfunction.
Role of Imaging and Biomarkers in VOD Diagnosis
The EBMT criteria emphasize the role of imaging, particularly ultrasound, in vod diagnosis, especially for late-onset VOD/SOS and in children. Ultrasound is readily available, cost-effective, and can be performed bedside to assess parenchymal and vascular changes. While ultrasound is recognized by EBMT for diagnostic confirmation, its role is primarily confirmatory when clinical signs are already apparent. Doppler ultrasound can detect signs of portal hypertension, such as ascites, hepatomegaly, splenomegaly, and portal vein dilatation. Scoring systems like the Lassau score and HokUS-10, based on ultrasound parameters, have been proposed to improve diagnostic accuracy, but require further validation and expertise in sonography. Contrast-enhanced ultrasound is being explored to assess hepatic vascularization and treatment response.
Magnetic resonance imaging (MRI) and computed tomography (CT) are gold standard techniques for liver lesion identification and staging, and are valuable in post-HSCT VOD/SOS. However, logistical challenges, particularly in critically ill patients, can limit their broader use in routine vod diagnosis.
Liver biopsy, while providing histological confirmation, is invasive and carries risks, especially in thrombocytopenic patients. Transjugular biopsy can reduce bleeding risk and allow hepatic venous pressure gradient (HVPG) measurement. HVPG measurement is a specific tool for vod diagnosis, with values >10 mm Hg predictive of VOD/SOS. However, its invasive nature limits routine application.
Non-invasive liver stiffness measurement (LSM) by elastography, particularly transient elastography (TE), is emerging as a promising tool in vod diagnosis. LSM correlates well with HVPG and has been used to stage liver diseases. Studies show that LSM values increase significantly in patients developing VOD/SOS, often preceding clinical diagnosis by 1 to 15 days. LSM also decreases with defibrotide treatment response. While promising for preclinical vod diagnosis and treatment monitoring, LSM has limitations related to operator expertise, ascites, and body mass index. Ongoing trials, like the Italian “ElastoVOD/SOS Study,” are further evaluating LSM’s prognostic role in a multicenter setting.
Several biomarkers are being investigated for vod diagnosis and risk prediction, including markers of hemostasis and coagulation (e.g., plasminogen activator inhibitor 1 [PAI-1]) and endothelial injury (e.g., von Willebrand factor, thrombomodulin, hyaluronic acid [HA]). PAI-1 is the most studied biomarker, with elevated levels associated with VOD/SOS risk and decreased levels correlating with treatment response. However, proteomic approaches have identified other potential biomarkers, such as l-ficolin, HA, and vascular cell adhesion molecule 1. Currently, biomarker data for vod diagnosis remain inconclusive for widespread clinical application.
Incidence and Risk Factors for VOD/SOS
The reported incidence of VOD/SOS varies widely (2-60%) due to differences in patient populations, transplant procedures, and diagnostic criteria. VOD/SOS incidence is generally higher in children than adults, although some studies report lower pediatric incidence rates.
Risk factors for VOD/SOS are broadly categorized as patient-related and transplantation-related. Patient-related risk factors include younger age, poor Karnofsky index, pre-existing liver disease, abnormal liver function tests, advanced hematological disease, second transplant, thalassemia, ferritin levels, and abdominal radiation. The use of immunotherapies like gemtuzumab ozogamicin and inotuzumab ozogamicin for acute leukemia treatment is associated with a significantly increased VOD/SOS risk, particularly post-HSCT.
Transplantation-related risk factors include allogeneic HSCT, mismatched/haploidentical transplant, T-replete transplants, and myeloablative conditioning regimens containing busulfan or total body irradiation. Risk scoring systems, such as the Center for International Blood and Marrow Transplant Research risk score, incorporate factors like age, hepatitis B/C serology, Karnofsky index, sirolimus use, disease status, and conditioning regimen to predict VOD/SOS risk. However, these scores may not fully account for pre-transplant therapies impacting VOD/SOS risk. Prospective validation and refinement of risk factors are ongoing to improve risk stratification and guide preventative strategies and vod diagnosis protocols.
Treatment and Outcome of VOD/SOS
VOD/SOS treatment involves supportive care, intensive care, and specific therapy with defibrotide. Supportive care focuses on managing fluid balance, ascites, pleural effusion, hypoxia, pain, and renal dysfunction. Defibrotide is the only approved drug for moderate/severe VOD/SOS. It is a mixture of polydeoxyribonucleotides derived from porcine intestinal mucosa, with pleiotropic mechanisms including endothelial protection, antithrombotic, and profibrinolytic effects.
Clinical trials and compassionate use programs have demonstrated defibrotide’s efficacy and safety in treating VOD/SOS, particularly post-HSCT. Studies show improved 100-day survival and complete response rates in defibrotide-treated patients compared to historical controls or supportive care alone. Earlier defibrotide initiation is associated with better survival. While generally well-tolerated, defibrotide can be associated with hemorrhagic events.
Corticosteroids have been used in VOD/SOS management, but their use is debated due to infection risk. Tissue plasminogen activator and N-acetylcysteine are not recommended due to bleeding risks and lack of efficacy. For refractory VOD/SOS, treatment options are limited and outcomes are poor. Transjugular intrahepatic portosystemic shunting (TIPS) and orthotopic liver transplantation are rarely considered in severe, refractory cases.
Prophylaxis of VOD/SOS
Prophylactic strategies for VOD/SOS have been explored, including heparin, antithrombin, prostaglandin E1, pentoxifylline, and ursodeoxycholic acid (UDCA). Ursodeoxycholic acid is recommended by some guidelines for prophylaxis. While heparin has been studied extensively, results are inconclusive. Antithrombin and pentoxifylline have not shown efficacy. Prostaglandin E1 use was abandoned due to toxicity. Ursodeoxycholic acid has shown promise in reducing VOD/SOS incidence in some randomized trials and meta-analyses, with a favorable safety profile.
Defibrotide prophylaxis has been investigated in retrospective studies and a prospective randomized trial in children. This pediatric trial demonstrated a significant reduction in VOD/SOS incidence with prophylactic defibrotide in high-risk children undergoing HSCT. Based on these findings, guidelines recommend defibrotide prophylaxis in high-risk pediatric HSCT recipients. However, evidence for defibrotide prophylaxis in adults is less conclusive, and ongoing trials are needed to clarify its role in adult VOD/SOS prevention. Whether prophylaxis or early treatment strategies are more effective overall remains an area of active research.
Conclusions
Vod diagnosis of VOD/SOS remains primarily clinical, although advancements in imaging and biomarkers are evolving the diagnostic landscape. Ultrasound is a valuable imaging modality, particularly for late-onset VOD/SOS and in children. Elastography shows promise for non-invasive vod diagnosis and treatment monitoring. Biomarkers are under investigation but not yet validated for routine clinical use. Despite improved diagnostic criteria systems, differential vod diagnosis remains challenging, and invasive methods are not always feasible.
Multidisciplinary approaches integrating radiology, hepatology, intensive care, and nephrology are crucial for optimal VOD/SOS management. Mortality rates for VOD/SOS, particularly with MOD, have decreased in recent years, likely due to improved intensive care, multidisciplinary teams, risk stratification, and earlier treatment with defibrotide. Continued research into risk factors, diagnostic tools, and preventative strategies is essential to further improve outcomes in patients at risk for or diagnosed with VOD/SOS. Enhanced vod diagnosis and timely intervention are key to reducing the morbidity and mortality associated with this serious complication of HSCT and other medical interventions.
Author Contributions
FBon and AC conceived and designed the study. FBon wrote the first draft. AC, MS, FBar, ID, FR, and MC wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.
Conflict of Interest
FBon and AC participated on advisory boards and received speaker fees from JAZZ Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
Acknowledgments
The authors acknowledged BolognAIL and REUSE WITH LOVE for supporting the Transplant Program at the Hematology Department Seràgnoli in Bologna; the authors thank Dr. Rita Bertoni and Dr. Enrica Tomassini for the technical support.
