Sinusoidal obstruction syndrome (SOS) is a kind of rare liver disease which is characterized by damage to small hepatic vessels, affecting particularly the sinusoidal endothelium. Due to the special etiology and high mortality, early diagnosis of SOS is significant for clinical survival and prognosis.

To generalize the common etiologies and clinical symptoms of SOS and summarize the characteristic magnetic resonance imaging (MRI) features so as to provide more valuable information for early diagnosis of SOS.

We searched PubMed, Web of science, Wanfang Data, China Knowledge Resource Integrated, VIP, and Cochrane Library databases without a limiting period and the types of articles. The search process mainly revolved around the etiologies, common clinical symptoms, and MRI imaging features of SOS. Ultimately, 29 full articles were included in this review and 222 articles were excluded.

Eleven case reports included 13 patients. The etiologies of these patients including chemotherapy (5/13), medicinal herbs containing pyrrolidine alkaloids (PAs, e.g. Tusanqi) (4/13), hematopoietic stem cell transplantation (HSCT) (2/13), drug toxicity (6-thioguanine) (1/13), and “poppers”, a recreational drug used during anal intercourse (1/13). Eighteen case series including 497 patients, and SOS in 465 (93.6%) patients was caused by PAs. Ascites, abdominal pain and swelling, jaundice were the most common clinical symptoms. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), total bilirubin (TBil), direct bilirubin (DBil), and prothrombin time (PT) had varying degrees of elevation. Heterogeneous signals on T1 weighted imaging/T2 weighted imaging (T1WI/T2WI), heterogeneous enhancement of liver parenchyma, ascites, hepatomegaly, narrowing and blurring of intrahepatic inferior vena cava and three main hepatic veins, edema around the portal vein, and gallbladder wall edema were the most common MRI imaging features of SOS.

In the West, SOS was mostly secondary to HSCT. Some SOS developed in the process of chemotherapy for hepatic metastatic tumor. A few SOS were caused by toxicity of certain drugs. In the East, Tusanqi was a major cause of SOS. Ascites, abdominal pain and swelling, jaundice were the common clinical symptoms. Elevations of ALT, AST, GGT, ALP, TBil, and DBil could be used as predictors of liver function damage. Numerous characteristic MRI imaging features could provide more valuable information for early diagnosis of SOS.

Sinusoidal obstruction syndrome (SOS) is a rare liver vascular injury disease, characterized by damage to small hepatic vessels, affecting particularly the sinusoidal endothelium, which result in complications such as intrahepatic congestion, liver damage, and portal hypertension[1]. SOS was previously called as hepatic veno-occlusive disease until some researchers suggested that the main site of toxic injury is hepatic sinusoidal endothelium rather than hepatic veins[2]. Hepatomegaly, ascites, and elevated serum bilirubin levels are the characteristic manifestations of SOS. In addition, severe SOS is associated with a high mortality rate and most deaths result from multi-organ failure[3].

Although liver biopsy is the gold standard for the diagnosis of SOS, leukopenia and poor liver function resulting from hematological diseases or advanced tumors make this operation difficult. The Baltimore criteria, the modified Seattle criteria, and the European Society for Blood and Marrow Transplantation criteria are the three main criteria for diagnosing SOS[4,5]. However, these criteria are usually appropriated for SOS secondary to haemopoietic stem cell transplantation (HSCT), including a little of clinical information but not involving imaging findings. In recent years, magnetic resonance imaging (MRI) has been increasingly used to detect and evaluate liver diseases. In 2017, Chinese scholars combined the etiologies of SOS in Chinese and proposed the new diagnostic criteria for SOS, namely, the Nanjing criteria. The criteria focus on the diagnosis of SOS caused by pyrrolidine alkaloids (PAs), and incorporate clinical information and imaging findings[6].

Considering the complexity of etiologies and the limitation of liver biopsy, non-invasive imaging methods are significant for SOS differential diagnosis. This systematic review collected the current research on SOS, aiming at generalizing the common etiologies and clinical symptoms of SOS and summarizing the characteristic MRI imaging features for providing more valuable information in SOS early diagnosis.

This article systematically reviewed the current available literature related to the etiologies, clinical symptoms, and MRI imaging findings of SOS. In the West, SOS was mostly secondary to HSCT, while some SOS developed in the process of chemotherapy for hepatic metastatic tumor. However, the toxic effects of some special drugs also resulted in the occurrence of SOS, although they have been rarely reported[8,9]. In the East, especially in China, SOS was often caused by Tusanqi, a plant containing PA that always be used in the herbal medicines. Ascites, abdominal pain and swelling, and jaundice were the common symptoms. ALT, AST, ALP, GGT, and TBil were the main laboratory indicators for diagnosing liver damage. Heterogeneous signals on T1WI/T2WI, heterogeneous enhancement of liver parenchyma, ascites, hepatomegaly, narrowing and blurring of inferior vena cava (IVC) and three main hepatic veins, edema around the portal vein, and gallbladder wall edema were the most common MRI imaging features of SOS.

Our article presents several advantages. First of all, this is the first systematic review that combined clinical information and MRI imaging features of SOS. Second, English and Chinese databases were retrieved at the same time for ensuring the comprehensiveness of this review. To avoid duplicate articles or data, the rigorous studies screening program was also developed. In addition, we formulated the unique quality evaluation criteria based on the nature of the included literature.

SOS was first reported as an early complication of HSCT in 1979[10]. The cause of the disease is usually associated with sinusoidal endothelial cell cytotoxicity induced by a series of conditioning treatments prior to HSCT. The overall incidence of SOS is related to the diagnosis criteria and type of transplantation, with an incidence of up to 60%[11]. Some risk factors for SOS related to HSCT have been identified, including existing liver disease (chronic hepatitis, liver fibrosis, and cirrhosis), prior history of liver radiant examination, and the effects of some drugs used in the process of conditioning[12]. In addition, Al Jefri et al[4] pointed out that if a patient was too young or too old, or accepted allogeneic transplantation, the possibility of morbidity was greatly increased. In our included literature, van den Bosch et al[13] reported 2 patients who received HSCT due to a history of leukemia. Both of the patients had no history of chronic liver disease, and one of the patients was only 17 years old. However, both of the patients developed severe abdominal pain, hepatomegaly, and ascites approximately 2 wk after receiving HSCT, and the patients who received allogeneic transplantation progressed rapidly to upper gastrointestinal bleeding. Therefore, we believed that the occurrence of these 2 SOS cases is consistent with that mentioned by Al Jefri et al[4].

In recent years, preoperative chemotherapy has been widely used as a primary means of prolonging the survival rate of patients with liver metastasis from gastrointestinal cancer, especially colorectal cancer[14,15]. Whereas, the use of several cytotoxic agents has been reported to link with irreversible liver damage[16]. Oxaliplatin, as an important composition of the modern chemotherapy regimens, has been proven several times in relation to the incidence of SOS[17-19]. Indeed, out of 13 patients in 11 case reports, 5 patients were related to chemotherapy for liver metastasis from colorectal cancer and gastric adenocarcinoma[17,18,20,21]. All the patients received oxaliplatin-based adjuvant chemotherapy or S-1 and oxaliplatin (SOX) regimen chemotherapy. Five patients were identified with SOS during the chemotherapy cycle from 4 wk to 11 wk. All the 5 patients had abnormalities in laboratory indicators and moderate to severe splenomegaly. Overman et al[22] have shown that a 50% increase in spleen volume after oxaliplatin chemotherapy can be used as a predictor of SOS. These studies suggested that SOS should be considered if the cancer patient suddenly presented signs of splenomegaly or TBil elevation or persistent thrombocyte decline after a period of chemotherapy.

Furthermore, an animal study revealed that hepatic sinusoidal endothelial cells were equally sensitive to the toxic effects of PAs[23]. It has been reported that PAs-containing medicinal herbs (Tusanqi) can cause SOS[7,24]. A systematic review[7] has demonstrated that Tusanqi is a principal cause of SOS in China and the disease could develop within several days. Moreover, the elevation levels of bilirubin and ALT were significantly associated with poor outcomes. As showed in our study, 465 (93.6%) of the 497 patients were caused by Tusanqi, and these patients were almost Chinese. Most of them used Tusanqi soaked in wine to relieve body pain or to treat traumatic injury, and some others took it as a nutritional supplement. The duration of intake of Tusanqi ranged from 3 d to 4 years. The differences in onset time may be linked to personal physique and dose and mode of the medicine herbs. In addition, we found that patients caused by Tusanqi more likely presented obvious clinical symptoms. This might be related to the mixed ingredients of the herbal medicines, which might contain a variety of toxic ingredients in addition to PAs. However, we were not sure if intaking PAs-containing herbs for multiple doses as a nutritional supplement was associated with the toxic accumulation and severer symptoms.

In view of the limitations of current diagnostic criteria for SOS, more non-invasive diagnosis methods have to be confirmed. Recently, an increasing number of studies have demonstrated that many characteristic imaging features can improve the early diagnostic efficiency for SOS[25-27]. Through analyzing MRI features of our included cases, we found that heterogeneous signals on T1WI/T2WI, heterogeneous enhancement of liver parenchyma, ascites, hepatomegaly, narrowing and blurring of intrahepatic IVC and hepatic veins, periportal edema, and gallbladder wall edema were the major MRI features of SOS. Most of the patients presented patchy or diffuse abnormal enhancement of liver parenchyma, some were focused on the second hepatic portal and presented “clover”, “claw-shaped”, or irregular enhancement, and a few presented hepatic lobe predominant enhancement. “Clover” and “claw-shaped” types of enhancement were the two distinctive MRI imaging features. This may be related to the opening of small blood vessels around the main hepatic veins resulting from obstruction of the hepatic sinus outflow tract, which resulted in an increase in blood supply. Ascites, periportal edema, and gallbladder wall edema may be associated with blockage of portal blood flow and impaired liver function.

In addition, several studies[7,20,21] reported that the patients who underwent hepatobiliary scans presented diffuse or reticular low signals in the liver parenchyma. Yoneda et al[21] conducted a correlation analysis between organic anion transporting polypeptides 1B3 (OATP1B3) and function of hepatocytes. The results showed that SOS led to hepatocyte function impairment and the signal in the hepatobiliary phase was related to the degree of hepatocyte injury. In addition, Choi et al[28] and Arakawa et al[29] reported SOS cases of focal hepatic lesions during oxaliplatin chemotherapy, which were misdiagnosed as liver metastases. This result suggested that sometimes the focal hepatic lesions should be considered as the occurrence of SOS, and liver biopsy instead of hepatectomy should be used as the initial examination plan. Furthermore, Guo et al[30] indicated that the lesion areas presenting hypo-intensity on SWI and T2*WI were consistent with the abnormal enhancement in the portal vein phase in enhanced MRI. It may be related to the phenomenon that macrophages phagocytose and decompose red blood cells, and the decomposed red blood cells flow into the DISSE gap, which produces a large amount of hemosiderin. This result provided a new possibility for the diagnosis of SOS, especially for the patients with renal insufficiency or allergies to contrast agents.

This systematic review had several limitations. First, due to the low incidence of SOS, not enough high-quality literature was included in our study. Second, due to the lack of more complicate data, we were not able to analyze the relationship between MRI features and patient survival prognosis. In addition, some of the included literature was relatively obsolete, and the MRI models and parameters of each center were also different, which may lead to misjudgment of image results due to insufficient understanding of MRI signs.