Hepatic sinusoidal obstruction syndrome related to Tusanqi: clinical analysis of 19 cases

Herbal medicine hepatotoxicity: A new step with development of specific biomarkers

Objective To investigate the clinical features, diagnosis and treatment of Gynura segetum-related hepatic sinusoidal obstruction syndrome (HSOS). Methods From January 2010 to May 2017, 458 hospitalized patients with HSOS from 29 hospitals were enrolled, and among them 239 cases were Gynura segetum-related HSOS. The diagnostic value of clinical signs in Gynura segetum-related HSOS were evaluated by Seattle criteria which used in HSOS caused by hemopoietic stem cells transplantation. The pathological diagnosis of liver biopsy was taken as gold standard. The diagnostic value of computed tomography (CT)/magnetic resonance imaging (MRI) in Gynura segetum-related HSOS was also investigated. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy and Kappa value were used for the assessment of diagnostic value. Cox regression analysis was performed for prognosis analysis. Results Among 362 patients with drugs-related HSOS, 239 cases (66.02%) was Gynura segetum-related HSOS and 232(97.07%) of the 239 patients with Gynura segetum-related HSOS presented with ascites. The diagnostic sensitivity and specificity of ascites in HSOS were 97.07% and 75.86%, respectively, and the Kappa value was 0.751. The diagnostic sensitivities of patchy map-like enhancement and (or) heterogeneous hypoattenuation of CT or inhomogeneous signal of MRI were 100.0% and 97.4%, respectively; and the specificities were 88.9% and 100.0%, respectively, and both of the Kappa value were more than 0.75, with excellent consistency. The accuracies of patchy enhancement, heterogeneous hypoattenuation of CT or inhomogeneous signal of MRI and ascites were all over 90%. Among 239 patients with Gynura segetum-related HSOS, 229 (95.82%) patients were treated with hepatoprotectants and diuretics, and 105 (43.93%) patients received anticoagulant drugs. The mortality rate was 8.37% (20/239). The percentage of patients with no improvement or deterioration was 17.57% (42/239). Increased total bilirubin and lactic dehydrogenase levels were related with poor prognosis (the relative risk was 1.012 and 1.009, respectively; both P<0.05). Conclusions Gynura segetum is a major cause of hospitalized patients with HSOS in China. Ascites is the major clinical manifestation. The patchy enhancement, heterogeneous hypoattenuation of CT or inhomogeneous signal of MRI are the main CT/MRI signs of HSOS. There are no reliable and effective treatments for Gynura segetum-related HSOS and the mortality is relatively low. Key words: Hepatic sinusoidal obstruction syndrome; Pyrrolizidine alkaloids; Multicenter study; Retrospective studies

Objective To analyze the clinical features of hepatic veno-occlusive disease (HVOD) and to explore the diagnosis criteria and treatment.Methods A total of 50 cases of HVOD administrated at The First Affiliated Hospital of College of Medicine,Zhejiang University from August 2008 to August 2011 were analyzed for etiology,clinical manifestation,laboratory examination,image,pathological features and treatment.Results Among the 50 HVOD cases,38 cases (76％)had a history of taking Gynura segetum.The main clinical manifestations were ascites,hepatomegaly,right upper quadrant pain,jaundice,and weight gain.Laboratory examinations indicated liver function injury and increased serum CA125 level.Color Doppler ultrasound showed hepatomegaly,decrease in diameter of hepatic vein and slow blood flow.The computed tomography scan suggested hepatomegaly,enhanced scan showed liver inhomogeneous enhancement at portal and delayed phase,map-like changes and markedly decrease in diameter of hepatic vein.Pathological examination suggested hepatic sinusoid congestion,central vein stenosis and vessel wall thickening.The main therapy was anticoagulant treatment.One case cured,33 cases improved,13 cases uncured and three cases died.Conclusions HVOD because of taking Gynura segetum is common in Zhejiang Province,which can be diagnosed according to medical history,clinical manifestations, and typical image characteristic.However,diagnosis of the atypical cases still needs liver biopsy.Anticoagulation therapy can achieve better efficacy. Key words: Hepatic veno-occlusive disease; Alkaloids; Drugs,Chinese herbal; Biopsy,needle; Anticoagulants

Liver Injury after Autologous Hematopoietic Stem Cell Transplant: DILI and SOS

Herbs and dietary supplement-induced liver injury (HILI) is the leading cause of drug-induced liver injury in China. Among different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-producing herb Gynura japonica contributes significantly to HILI by inducing hepatic sinusoidal obstruction syndrome (HSOS), a liver disorder characterized by hepatomegaly, hyperbilirubinemia, and ascites. In China, G. japonica has been used as one of the plant species for Tu-San-Qi and is often misused with non-PA-producing Tu-San-Qi (Sedum aizoon) or even San-Qi (Panax notoginseng) for self-medication. It has been reported that over 50% of HSOS cases are caused by the intake of PA-producing G. japonica. In this review, we provide comprehensive information to distinguish these Tu-San-Qi-related herbal plant species in terms of plant/medicinal part morphologies, medicinal indications, and chemical profiles. Approximately 2156 Tu-San-Qi-associated HSOS cases reported in China from 1980 to 2019 are systematically reviewed in terms of their clinical manifestation, diagnostic workups, therapeutic interventions, and outcomes. In addition, based on the application of our developed mechanism-based biomarker of PA exposure, our clinical findings on the definitive diagnosis of 58 PA-producing Tu-San-Qi-induced HSOS patients are also elaborated. Therefore, this review article provides the first comprehensive report on 2214 PA-producing Tu-San-Qi (G. japonica)-induced HSOS cases in China, and the information presented will improve public awareness of the significant incidence of PA-producing Tu-San-Qi (G. japonica)-induced HSOS and facilitate future prevention and better clinical management of this severe HILI.

Objective To analyze the clinical characteristics, diagnosis and treatment of Gynura segetum-related hepatic sinusoidal obstruction syndrome (HSOS), so as to provide guidance for early diagnosis and effective treatment. Methods A retrospective analysis was performed on the clinical manifestations, laboratory examinations, treatment and prognosis of 53 patients with HSOS, which were hospitalized in the First Affiliated Hospital of Zhengzhou University from January 2013 to March 2018. Results The main clinical manifestations of HSOS were abdominal distension, jaundice, hepatomegaly. Laboratory examination showed different degrees of liver impairment and coagulation abnormalities. The typical imaging manifestations were ascites, patchy liver enhancement and narrowing hepatic vein. Twenty-three patients were treated by symptomatic therapy, 20 patients received anticoagulant drugs, and 10 patients received transjugular intrahepatic porto systemic stent-shunt (TIPS). After treatment, 22 cases were cured, 17 cases were improved and 14 cases were uncured. Alanine transaminase, aspartatetransaminase, total bilirubin, direct bilirubin, prothrombin time, D-Dimer and Child grade levels were associated with poor prognosis of HSOS (P<0.05). Conclusions A history of Gynura segetum intake supplies a key clue for diagnosing HSOS. Due to the lack of specific clinical manifestation, imaging is essential for diagnosis of HSOS. It is necessary for atypical cases to perform liver biopsy. Improving circulation and anticoagulation have good curative effects on the disease. TIPS is effective for patients when medicine treatment failed. While the severity of liver impairment are significantly associated with poor outcome. Key words: Sinusoidal obstruction syndrome; Gynura segetum; Anticoagulation; Transjugular intrahepatic portosystemic shunt

Herbal hepatotoxicity

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening syndrome, and a cause is exposure to pyrrolizidine alkaloid (PA)-containing products. It is well-established that retrorsine (RTS), a representative Pas, insults hepatic sinusoidal endothelial cells and ensues congestion of hepatic sinusoids. However, little known about the impact of Pas on gut microbiota and intestinal barrier and inflammation in HSOS. Mice were gavaged with or without nonabsorbable antibiotics (ABX), followed by a single dose of RTS. The gut microbiota was examined by 16S rDNA sequencing. ABX pretreatment significantly reversed RTS-induced liver damage. RTS altered gut microbiota composition, increasing Gram-negative bacteria and resulting in a sharp elevation of circulating lipopolysaccharides (LPS) in HSOS mice. Gut decontamination with ABX alleviated RTS-induced intestine inflammation, protected against disruption of the intestinal epithelial barrier and gut vascular barrier (GVB), and suppressed hepatic LPS-NF-κB pathway activation in RTS-induced HSOS. Importantly, the LPS level was positively correlated with MELD score in patients with HSOS. Elevated LPS in patients with HSOS confirmed that Gram-negative bacteria were involved in the pathogenesis of HSOS. RTS, a PA, cooperated with gut dysbiosis to cause intestinal inflammation and gut barrier compromise that increased transport of gut-derived LPS into the liver through the portal vein, which contributed to the pathology of HSOS. Modulating the gut microbiota, protecting the intestinal barrier, and suppressing intestinal inflammation with prebiotics or antibiotics might be a useful pharmacologic intervention in HSOS.

THE PATHOLOGY, DIAGNOSIS, AND TREATMENT OF HEPATIC VENO‐OCCLUSIVE DISEASE: CURRENT STATUS AND NOVEL APPROACHES

Understanding the Similarities and Differences between Hepatic and Pulmonary Veno-Occlusive Disease

Hepatic sinusoidal obstruction syndrome (HSOS) induced by a Chinese medicinal herb Tusanqi is increasingly being reported in recent years. The aim of the study was to investigate the possibility of using blood pyrrole-protein adducts test as a confirmatory diagnostic method. Patients with HSOS according to international diagnostic criteria associated with Tusanqi from January 2006 to August 2010 in Zhongshan Hospital Fudan University were included and clinical features were collected. Pyrrole-protein adducts in blood sample were determined with ultra performance liquid chromatography-mass spectrometry (UPLC-MS) while pyrrolizidine alkaloids (PAs) in available herbal preparations were analyzed by high performance liquid chromatography-ultraviolet (HPLC-UV). Five patients (age 41-72 years, median age 54 years, all women) were included. Ascites (5/5), jaundice (5/5) and hepatomegaly (4/5) were common manifestations. The imaging features were diffused, patchy hepatic enhancement, periportal edema and ascites. Pathology ascertained that blood flow was obstructive at the site of sinusoid. PAs (Seneionine and seneciphylline) were identified in all the three available herbal preparations ingested by the HSOS patients. Pyrrole-protein adducts were unequivocally found in all the five blood samples. Two patients recovered, two developed chronic illness and one died due to liver failure and hepatic encephalopathy. The detection of blood pyrrole-protein adducts using a UPLC-MS approach is a specific, reliable, unambiguous and confirmatory test for HSOS induced by PA, and should be used together with the conventional HSOS clinical diagnostic criteria for the definitive diagnosis of PA-induced HSOS.

Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice.

Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9

Objective To study the role of NOD-like domain (NLRP)3 inflammasome in hepatic venoocclusive disease (HVOD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) undergoing different pre-treatments.Methods A total of 50 specific-pathogen free (SPF) male BALB/c (H 2Kd) mice were included in this study,and randomly divided into study group (n=40) and control group (n=10) by computer.According to the differences of allo-HSCT pre-treatment programs,study group mice were divided into two groups:busulfan/cyclophosphamide (BU/CY) pre-treatment group (n =20) and total body irradiation (TBI) pre-treatment group (n=20).The experiment was disposed with the ethical standard.On the 15th day after allo-HSCT,recipient mice in each group were sacrificed and collected bone marrow and whole liver samples,in order to detect the chimeric rate and white blood cell (WBC) count,and calculate liver index.The liver samples were divided into two parts.One part of liver samples were observed the histologic pathology by hematoxylin-eosin (HE) staining,Masson's trichrome staining and immunohistochemistry,and gave pathological score of HVOD to evaluate the degree of liver injury.Another part of liver samples were assessed relative expression levels of cytokine interleukin (IL)-1β,-18 by realtime fluorescence quantitative polymerase chain reaction (PCR) to study the role of inflammatory injury to HVOD.Then,liver samples were assessed relative expression levels of cysteine aspartic proteases (Caspase)-1 and NLRP3 to study role of NLRP3 in HVOD after allo-HSCT undergoing different pretreatments.Results ① Hematopoietic stem cells had been successfully transplanted into study group mice with chimeric rate over 98.0％ on the 15th day after allo-HSCT.② The pathology injury of HVOD in BU/CY pre-treatment group was more than that of TBI pre-treatment group.In BU/CY pre-treatment transplantation group,liver index was below and 10 cases of HVOD samples were diagnosed severe HVOD;while in TBI pre-treatment group,5 cases of HVOD samples were diagnosed as medium HVOD and another 5 cases were diagnosed as severe HVOD.③ The relative expression levels of IL-1β,-18 in BU/CY pretreatment group were 13.9 times and 5.5 times of that in TBI pre-treatment group,so the inflammatory injury of BU/CY pre-treatment group was more serious than that of TBI pre-treatment group,and there were statistical differences between two groups (P＜0.05).④ Relative expression level of caspase-1 in BU/CY pre-treatment group was 19.5 times of that in TBI pre-treatment group,the relative expression level of NLRP3 in BU/CY pre-treatment group was 1.2 times of that in TBI pre-treatment group,and there was statistical difference between two groups (P＜0.05).Conclusions Thc relative expression level of NLRP3 in BU/CY pre-treatment group was more than that of TBI pre-treatment group,which accorded with the degree of liver injury.NLRP3 inflammasome played an important role in HVOD after allo-HSCT. Key words: NLRP3 protein, human; Cytokine; Busulfan; Cyclophosphamide; Total-body irradiation; Hepatic veno-occlusive disease

Hepatic veno-occlusive disease (HVOD) is a rare but severe condition characterized by the blockage of microscopic veins in the liver due to endothelial damage, leading to sub-endothelial thickening, edema, and fibrosis. Globally the cause of HVOD is primarily associated with pyrrolizidine alkaloid (PA) ingestion, radiation therapy, and post-transplant reactions. Similarly, in the Tigray region of Ethiopia, the disease's outbreak has been linked with contaminated harvests containing PA-producing seed called "Ageratum conyzoides". However, the perception and current experience of community members and healthcare providers on the cause and prevention strategies of the disease are not explored. To explore the perceptions and practices of community members and healthcare providers on HVOD in Tigray, Ethiopia. This qualitative study was conducted in the Tigray Region of Northern Ethiopia from January to February 2025. It employed a community and facility-based approach using in-depth interviews (IDIs), focus group discussions (FGDs), and key informant interviews (KIIs) to explore perceptions and current experiences on the causes and practice of preventive measures of HVOD. We selected five districts with high HVOD burdens. We included religious leaders and HVOD victims from the community members and healthcare leaders and professionals from the health facilities. A total of three FGDs, sixteen IDIs, and seven KIIs were conducted and data was analyzed thematically using Atlas.ti software. The community's understanding of HVOD is complex, recognizing it as a severe chronic disease but with uncertainty about its transmission and prevention. Our study identified three key themes: variability in knowledge among community members and healthcare providers regarding HVOD's causes, prevention, and treatment, alongside a notable lack of coordinated leadership and support from healthcare providers, political leaders, and other stakeholders. Participants expressed frustration over the absence of structured interventions for awareness, prevention, and treatment. Additional barriers included skepticism about Ageratum conyzoides as the cause, social stigma, traditional beliefs, political instability, healthcare system weaknesses, and economic challenges. Acceptance of scientific interventions was uneven, shaped by varying levels of trust and resistance. Participants emphasized the need for targeted healthcare provider training, stronger community engagement in awareness and planning, and formal integration of HVOD into national health programs to improve resource allocation and coordination. These findings highlight the complex challenges and inform strategies for more effective HVOD control. Hepatic veno-occlusive disease (HVOD) is a significant public health issue in Ethiopia, which is exacerbated by misconceptions and systemic healthcare challenges. To address this, strengthening healthcare systems and community engagement through awareness campaigns are crucial. Integrating HVOD into the national public health emergency management programs with multi-sectoral collaboration could be essential for its effective management.