EASL Clinical Practice Guidelines

Sinusoidal obstruction syndrome – veno-occlusive disease of the liver

Sinusoidal obstruction syndrome (SOS, previously named veno-occlusive disease or VOD), is characterized morphologically by a loss of sinusoidal wall integrity. Sinusoidal endothelial cells at first become injured and detach from the wall (endothelium denudation), followed by cell embolization and sloughing towards central zones of hepatic lobules, and a subsequent sinusoidal congestive obstruction by outflow block. According to the level of obstruction, various degrees of centrilobular hepatocellular necrosis may occur. SOS may also be associated with one or more other lesions such as centrilobular perisinusoidal and endovenular fibrosis, peliosis and nodular regenerative hyperplasia (NRH).

SOS is a well-established hepatic complication of myeloablative regimens used in the setting of haematopoietic stem cell transplantation (HSCT). A large number of drugs and toxins have also been associated with SOS including several chemotherapeutic agents used in adjuvant or neo-adjuvant treatments of solid cancer, or immunosuppressors applied in the context of organ transplantation or inflammatory bowel diseases. Total body or hepatic irradiation and platelet transfusion containing ABO-incompatible plasma represents other reported associated conditions (Table 5). SOS can engender significant morbidity and mortality in all these settings [[54], [151]]. Pathogenesis of SOS is not yet conclusively established. The establishment of a rat model based on monocrotaline (pyrrolizidine alkaloid) gavage was a milestone and lead to a better understanding of SOS pathogenesis, both at the morphological and biochemical levels [152].

Table 5
Major causes of sinusoidal obstruction syndrome.



Incidence

Many studies have been based on clinical criteria whose specificity and sensitivity may vary greatly according to the context. SOS incidence differs considerably according to patient risk factors, type of drug regimen, number of cycles of chemotherapy, diversity in clinical or in histological diagnostic criteria.

SOS incidence has declined in HSCT from 50% [153] to currently about 14% [154], and in solid transplantation as well. Decreased incidence has been attributed to the development of prophylactic therapy, avoidance of cyclophosphamide containing regimens, and lower doses of total body irradiation in HSCT, and lesser use of azathioprine in solid organ transplantation. However, other drugs and settings may be responsible for SOS (Table 5). The incidence is these cases are less well-established.

Clinical manifestations and outcome

The typical signs and symptoms are; weight gain due to fluid retention with or without ascites, tender hepatomegaly and jaundice [155]. Clinical presentation may however range from the absence of symptoms to features of PH and severe multiorgan dysfunction that may lead to death.

In the context of HSCT, clinical onset usually occurs in the first 20 days in SOS due to cyclophosphamide, and later with other regimens. According to clinical course severity, SOS may be subdivided into three forms: mild SOS (self-limiting disease not requiring treatment); moderate SOS (resolving disease nevertheless requiring treatment notably for fluid retention); and severe SOS (disease not resolving after day 100 despite treatment, that may lead to death). Major parameters of poor outcome (mostly validated for cyclophosphamide-related SOS), are high serum bilirubin and level of weight gain. Other parameters are aminotransferase rise, high hepatic venous pressure gradient, renal function and multiorgan failure. Death is most commonly caused by renal, cardiopulmonary or liver failure. Mortality rate at 100 days is 9% in mild cases to near 100% in patients with clinically severe SOS.

In the context of oxaliplatin chemotherapy regimen (used for downstaging colorectal liver metastasis (CRLM) before surgical hepatic resection), SOS is associated with a decreased liver metastases imaging detections [155], an increased operative bleeding [156], and post-operative liver dysfunction or a delay in liver regeneration [[157], [158]].

The time frame for regression of SOS and associated lesions (centrilobular fibrosis and NRH) remains unknown. SOS and NRH persisted histologically in the setting of a two stage hepatectomies for CRLM (where liver surgery of the same patient is performed with an interval of 4 to 7 weeks with no chemotherapy applied during this interval) [159], as in several cases that underwent iterative hepatic surgery for recurrence with a gap of several months. PH, evaluated by spleen size, improved only between 1 to 3 years after completing oxaliplatin treatment [160]. It is noteworthy that in several cases persistence or progression of a histological lesion and signs of PH have been observed.

Despite an apparently indolent initial course, delayed complications of SOS may occur. In toxic oil syndrome, PH appeared 2.5 years after consuming the oil, as with azathioprine and 6-thioguanine, sinusoidal lesions persist at biopsy and become symptomatic over time.

Diagnosis

Currently, the absence of specific clinical signs or serological diagnostic tool makes recognition of SOS challenging. Diagnosis is essentially based on a high index of clinical suspicion, after exclusion of other potential mimicking causes (Table 6), resulting in various levels of diagnostic accuracy (up to 20% of patients cannot be clinically diagnosed with certainty) and potential risks of error. Clinical features for diagnosis have been formalized in the Seattle or Baltimore criteria; their sensitivity and specificity have not been well-defined and their use in the different settings of SOS aetiology have not been evaluated. According to regimens, delay in clinical onset of SOS after initiation of therapy varies and some features may be lacking.

Table 6
Major differential diagnosis of sinusoidal obstruction syndrome.


Increase in serum bilirubin is a sensitive but not specific marker of SOS. Other markers have been proposed, including serum procollagen, plasminogen activator inhibitor-1, platelet count less than 167,000/μl, high APRI or FIB-4 scores, but have not been independently validated yet [161].

There are no definitive ultrasound features for early SOS diagnosis. Doppler ultrasound may show signs of PH, and liver and spleen enlargement [[162], [163], [164]]. Reversal of flow in the portal vein and monophasic flow in the hepatic vein have been used to diagnose SOS but lacks sensitivity [165]. CT scan is not recommended because of the toxicity of contrast agents. MR imaging may show patients hepatic veins and patchy signal enhancement compatible with the diagnosis of histologically severe SOS [[166], [167], [168]].

Transjugular liver biopsy combined with measurement of the wedged hepatic venous pressure gradient is of major help in confirming the diagnosis [[169], [170], [170]]. Regardless of its cause, SOS has similar pathological features [171]. According to the level of obstruction, various degrees of centrilobular hepatocellular necrosis may occur. SOS may also be associated with centrilobular perisinusoidal and endovenular fibrosis, peliosis and NRH [172]. Except peliosis, all these lesions are morphologically distinct from sinusoidal changes, although they appear to be related to its severity [[169], [172]] or represent late lesions. Occlusion of the centrilobular veins occurs only in 50% of patients with mild to moderate SOS and up to 75% of patients with severe SOS after HSCT [169], and in around 50% of patient with oxaliplatin-related SOS [[156], [171], [172]]. Therefore, the alternate terms of SOS was proposed in replacement of VOD. Percutaneous biopsy is often contraindicated by thrombocytopenia, coagulopathy or ascites.

Despite patchy distribution of SOS lesions, liver biopsy findings have been reported to influence treatment decisions in around 90% of patients [[173], [174]]. Combining biopsy with haemodynamic evaluation helps in the overall sensitivity. Hepatic venous pressure gradient >10 mmHg has a sensitivity of 52% and a specificity of 91% with a positive predictive value greater than 85% for the diagnosis of SOS in the context of HSCT. Despite advanced imaging modalities, histology currently remains the optimal means for the diagnosis of fibrosis and NRH. From a pathologist’s perspective, the diagnosis of NRH can be challenging and reticulin staining is needed.

Prophylaxis and treatment

Recognition of risk factors is helpful for the prevention of SOS [[161], [175]]. Risk factors include pre-existing liver disease, previous episode of SOS and type of regimen; and, in the context of solid cancer treatment (in particular colorectal liver metastasis), abnormal preoperative gamma-glutamyl transpeptidase, age, female gender, indocyanin green retention rate at 15 minutes, number of cycles of chemotherapy and a short interval between the end of chemotherapy and surgical liver resection. Polymorphisms of the glutathione S-transferase gene (coding for enzymes catabolizing chemotherapeutic drugs) have been associated with a risk of SOS [176].

Reduction of the intensity of myeloablative regimens or choice of regimens that carry lower risk of SOS has to be counterbalanced with a possible lower anti-tumoral efficacy or appearance of other complications.

Defibrotide (single-stranded oligodeoxyribonucleotides mixture extracted from porcine intestinal mucosal DNA with multiple antithrombotic, fibrinolytic and angiogenic properties) has demonstrated a benefit for SOS prophylaxis in a randomized study in pediatric HSCT [177]. A meta-analysis of the effects of heparin showed no positive effect [178].

Indications for treatment of SOS depend on its clinical severity. There are still no solid data to give firm recommendations [179]. Treatment of SOS relies mostly on supportive care with therapy of fluid retention, sepsis and organ failure. TIPS, surgical shunting and liver transplantation have been used essentially in individual cases as a rescue therapy; more data and prospective studies are needed to confidently indicate the value of this treatment approach in SOS. Liver transplantation is however limited by the underlying malignancy which may itself be a contraindication and should be proposed only to patients with favourable oncologic prognosis or non-oncologic aetiology.