Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice / 中国天然药物

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.

Relationship between hepatic venous pressure gradient and parameters of Doppler ultrasound in 68 patients with pyrroidine alkaloid-related hepatic sinusoidal obstruction syndrome / 中华消化杂志

Objective:To investigate the relationship between hepatic venous pressure gradient (HVPG) and parameters of Doppler ultrasound in patients with pyrroidine alkaloid-related hepatic sinusoidal obstruction syndrome (PA-HSOS).Methods:From February 17, 2017 to April 22, 2020, the clinical data of 68 patients with PA-HSOS who underwent HVPG manometry and Doppler ultrasound examination at Drum Tower Hospital, the Affiliated Medical College of Nanjing University were retrospectively analyzed, which included HVPG, Drum Tower severity scoring (DTSS), time from PA-HSOS related symptoms appeared to diagnosis after taking pyrroidine alkaloid (hereinafter referred to as diagnosis time), and parameters of Doppler ultrasound induding portal vein trunk diameter (PD), peak portal vein velocity (PPV), splenic vein trunk diameter (SD) and peak splenic vein velocity (PSV). Receiver operating characteristic curve (ROC) was used to determine the optimal cut-off value of HVPG for predicting non-response to anticoagulation therapy. Binary logistic regression was used to analyze the independent risk factors for non-response to anticoagulation therapy, and Kaplan-Meier survival curve was used to analyze the prognostic survival rate of patients with different HVPG levels. Unitary linear regression was applied to analyze the correlation of HVPG with PD, PPV, SD and PSV in patients with different HVPG levels, patients with mild, moderate and severe DTSS, and patients with diagnosis time >1 month or ≤ 1 month. Chi-square test was used for statistical analysis.Results:The results of ROC analysis showed that the optimal cut-off value of HVPG for predicting non-response to anticoagulant therapy was 20.165 mmHg(1 mmHg=0.133 kPa). The result of multivariate analysis indicated that high HVPG (HVPG>20.165 mmHg) was an independent risk factor for predicting non-response to anticoagulant therapy ( OR (95% confidence interval)=6.039(1.466 to 24.869), P=0.013). Kaplan-Meier survival curve demonstrated that prognostic survival rate of patients with high HVPG was lower than that of patients with low HVPG (HVPG≤20.165 mmHg) (78.4% vs.96.8%), and the difference was statistically significant( χ2=4.74, P=0.030). The results of unitary linear regression analysis showed that there was a negative correlation between HVPG and PPV in 68 patients with PA-HSOS( r=-0.330, P=0.006); HVPG was positively correlated with PD and SD in patients with high HVPG ( r=0.540 and 0.341, P=0.001 and 0.039); there was a negative correlation between HVPG and PSV in patients with mild DTSS ( r=-0.519, P=0.019), HVPG was negatively correlated with PPV in patients with moderate DTSS ( r=-0.400, P=0.014). In patients with diagnosis time ≤1 month, there was a negative correlation between HVPG and PPV ( r=-0.391, P=0.010). Conclusions:HVPG can assist in judging the response to anticoagulation therapy and the prognosis of patients with PA-HSOS. Parameters of Doppler ultrasound can help to assess the degree of HVPG elevation in patients with PA-HSOS under certain conditions.

Clinical impact of transjugular intrahepatic portosystemic shunt on refractory hepatic sinus obstruction syndrome caused by Gynura segetum / 中华肝胆外科杂志

Objective:To study the treatment outcomes of transjugular intrahepatic portal shunt (TIPS) on refractory hepatic sinus obstruction syndrome (HSOS) caused by Gynura segetum.Methods:The clinical data of 15 patients with refractory HSOS caused by Gynura segetum treated at the Department of Vascular Surgery, Henan Provincial People's Hospital from January 2017 to April 2021 were retrospectively analyzed. There were 7 males and 8 females, with ages ranging from 30 to 85 years, mean ± s. d. (61.2±14.1) years. Albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutamyl transferase, and portal vein pressure were compared before and after TIPS. The liver function and renal function of these patients were followed up.Results:When compared with pre-operation, the albumin, alanine aminotransferase, aspartate aminotransferase and other indexes were significantly improved after TIPS (all P<0.05). The portal vein pressure of 15 patients significantly decreased from the preoperative volume of (41.7±3.5) cmH 2O (1 cmH 2O=0.098 kPa) to (28.3±4.4) cmH 2O ( t=10.41, P<0.001). The preoperative liver function was Child-Pugh grade A in 1 patient, grade B in 8 patients, grade C in 6 patients. The postoperative Child-Pugh grading was grade A in 14 patients and grade B in 1 patient. Ascites, gastrointestinal bleeding, abdominal pain, abdominal distention and spontaneous peritonitis all disappeared in these 15 patients. Postoperative hepatic encephalopathy developed in 2 patients and hepatic myelopathy in 1 patient. Conclusion:TIPS for treatment of HSOS caused by Gynura segetum resulted in a rapid recovery of liver function, rapid symptomatic relief, with a low incidence of hepatic encephalopathy/hepatic myelopathy.

The role of serum pyrrole-protein adduct in evaluating the severity and predicting the anticoagulant efficacy in patients with pyrroidine alkaloid-related hepatic sinusoidal obstruction syndrome / 中华消化杂志

Objective:To explore the role of serum pyrrole-protein-adduct (PPA) in evaluating the severity and predicting the anticoagulant efficacy in patients with pyrrolidine alkaloid-related hepatic sinusoidal obstruction syndrome (PA-HSOS).Methods:From April 2018 to December 2019, the data of 48 patients with PA-HSOS admitted and treated at Drum Tower Hospital, Affiliated Medical College of Nangjing University were collected, which included PPA level, portal vein velocity (PVV), ascites grading, PA-HSOS severity grading (according to the new severity grading criteria for suspected hepatic sinusoidal obstruction syndrome in adults by the European Society of Blood and Bone Marrow Transplantation and adjusted) and the outcome of anticoagulation. Patients with acute onset (onset of symptoms within 1 month after consuming pyrrolizidine alkaloid-containing plants) were taken as research subjects. The combination of PPA with PVV or with ascites classification of PA-HSOS severity assessment model was fitted by logistic regression, and the logit values of 2 combination models were calculated, the formula was logit 1=0.034×PPA(nmol/L)+ 0.055×PVV(cm/s)-3.287, logit 2=0.039×PPA(nmol/L)-2.712×ascites grade 2 (Yes=1, No=0)-0.388×ascites grade 3 (Yes=1, No=0)-0.899. The patients received initial anticoagulation therapy at Drum Tower Hospital, Affiliated Medical College of Nanjing University were selected as research subjects. The anticoagulant efficacy prediction model of combination of PPA with serum creatinine (SCR) and with hepatic venous pressure gradient (HVPG) was fitted by logistic regression, and the logit value was calculated, the formula was logit 3=0.013×PPA(nmol/L)+ 0.064×SCR (mol/L)+ 0.542×HVPG (mmHg, 1 mmHg=0.133 kPa)-16.005. The predictive value of PPA in evaluating the severity of PA-HSOS and anticoagulant efficacy was evaluated. Receiver operating characteristic curve analysis was performed for statistical analysis. Results:The serum PPA level of 48 patients was 10.81 nmol/L (3.91 nmol/L, 32.04 nmol/L). Among them, 33 cases (68.8%) were mild PA-HSOS, 3 cases (6.2%) were moderate PA-HSOS, no severe PA-HSOS case and 12 cases (25.0%) were very severe PA-HSOS. Among 23 patients received initial anticoagulant therapy at Drum Tower Hospital, Affiliated Medical College of Nanjing University and with complete data, 8 patients responded and survived, and 15 patients did not respond (5 patients died, 1 patient relieved after continue anticoagulant therapy, and 9 patients survived after switching to anticoagulant therapy and transjugular intrahepatic portosystemic shunt (TIPS) treatment). One patient without initial anticoagulant therapy, survived after TIPS treatment because of the progress of the disease. Area under the curve (AUC) of PPA to assess the severity of acute onset PA-HSOS was 0.75, 95% confidence interval ( CI) was 0.52 to 0.98 ( P=0.047). When PPA≥45.519 nmol/L, the specificity and sensitivity in evaluating severe and very severe PA-HSOS was 100.0% and 57.1%, respectively. AUC of combination of PPA and PVV to assess the severity of PA-HSOS was 0.77, 95% CI was 0.55 to 1.00 ( P=0.032). When the logit of combination model≥0.180, the specificity and sensitivity in evaluating severe and very severe PA-HSOS was 71.4% and 81.8%, respectively. AUC of combination of PPA and ascites grade (grade 1, 2 or 3) to assess the severity of PA-HSOS was 0.85, 95% CI was 0.63 to 1.00 ( P=0.005). When the logit of combination model≥0.347, the specificity and sensitivity in evaluating severe and very severe PA-HSOS was 85.7% and 92.0%, respectively. AUC of combination of PPA, SCR and HVPG to predict anticoagulation efficacy was 0.85, 95% CI was 0.69 to 1.00 ( P=0.009). When the logit≥0.393, the specificity and sensitivity in predicting anticoagulation efficacy was 62.5% and 91.7%, respectively. Conclusions:PPA can be used to assess the severity of acute onset PA-HSOS patients, and combined with ascites grading can significantly improve its efficiency. PPA combined with SCR and HVPG can better predict anticoagulant efficacy.

Pathological Mechanism of HSOS in Rats Induced by Different Doses of Monocrotaline / 中国实验方剂学杂志

ObjectiveTo observe the pathological changes of hepatic sinusoidal obstruction syndrome （HSOS） induced by different doses of monocrotaline （MCT） in rats， investigate the dose and duration of modeling， and elucidate the mechanism. MethodA total of 72 male SD rats were randomized into normal group （n=12）， and low-， medium-， and high-dose MCT groups （n=20 per group， 80，120，160 mg·kg-1， respecctively）. In the model groups， different doses of MCT were intragastrically administered to induce the HSOS in rats. After 48 h and 120 h separately， rats in each group were sacrificed and sampling was performed. The survival rate of rats in each group was calculated， and the body weight， liver weight， and and serum liver function indexes of the rats were examined. The histopathological changes of the liver were observed based on scanning electron microscopy， hematoxylin and eosin （HE） staining， and Sirius red （SR） staining. Glutathione S-transferase （GST） activity， total superoxide dismutase （T-SOD） activity， and malondialdehyde （MDA） content of liver tissue homogenate were measured with microplate method. The expression of liver tissue-related indexes was detected by real-time polymerase chain reaction （PCR）， Western blot， and immunohistochemistry. ResultThe activity of serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in MCT groups rose with the increase in MCT dose （P<0.05， P<0.01） compared with that in the normal group. With the extension of modeling time， the activity of serum ALT and AST in the low-dose group decreased （P<0.01）， while the activity of them in the medium-dose and high-dose groups increased （P<0.01）. HE staining showed that hepatocyte necrosis， inflammatory cell infiltration， and erythrocyte accumulation in MCT groups. Electron microscopy demonstrated that fenestrae of liver sinusoidal endothelial cells widened and the sieve plates disappeared. Morever， the injury was worsened with the increase in MCT dose. In addition， the expression of CD44 in MCT groups was significantly reduced compared with that in the normal group （P<0.05， P<0.01）. SR staining showed that no positive staining was found in model groups after 48 h， while collagen deposition in portal areas and liver sinusoids could be seen in model groups after 120 h. MCT groups showed increase in MDA content and GST activity and decrease in T-SOD activity compared with the normal group， particularly the medium-dose and high-dose groups （P<0.01）， and the changes were dose-dependent after 120 h （P<0.01）. The protein expression of CD68 （pro-inflammatory macrophage marker） was raised with the increase in dosage， which was consistent with the results of immunohistochemistry （P<0.01）， while CD163 （anti-inflammatory macrophage marker） protein and mRNA expression was significantly decreased with the increase in dosage （P<0.01）. Western blot results showed that the expression of phosphorylated nuclear factor-κB/nuclear factor-κB （p-NF-κB/NF-κB） and phosphorylated protein kinase B/protein kinase B （p-Akt/t-Akt） was significantly increased in medium-dose and high-dose MCT groups （P<0.05，P<0.01）. The protein expression of α-smooth muscle actin （α-SMA） in liver tissues in MCT groups was significantly increased over time and with the increase in dose， and the mRNA expression of α-SMA， collagen type I α1 （Col1a1）， and collagen type Ⅳ α1 （Col4a1） showed the same trend （P<0.05， P<0.01）. The results of TUNEL staining showed that apoptotic cells were increased with the rise of MCT dose， while B-cell lymphoma-2（Bcl-2） /Bcl-2 associated X protein （Bax） was remarkably decreased （P<0.01）. ConclusionHSOS in rats induced by intragastric administration of different doses of MCT was aggravated with the increase of dosage. In the low-dose （80 mg·kg-1） MCT group， the liver healed spontaneously over time. However， liver damage caused by MCT of 120 mg·kg-1 and 160 mg·kg-1 aggravated over time， and even fibrosis and death occurred. The pathological mechanism of MCT-induced HSOS in rats may be that MCT triggered intense oxidative stress in liver tissue， thus activated pro-inflammatory macrophages to secrete large amounts of inflammatory factors， and further activated the NF-κB/Akt signalling pathway， leading to severe cell damage and death.

Diagnosis and treatment of hepatic sinusoidal obstruction syndrome after liver transplantation: a single-center experience / 器官移植

Objective To summarize the incidence, diagnostic and therapeutic experience of hepatic sinusoidal obstruction syndrome (HSOS) after liver transplantation. Methods Clinical data of 4 patients with HSOS after liver transplantation were retrospectively analyzed. The incidence, clinical manifestations, imaging and pathological characteristics of HSOS after liver transplantation were collected, and the treatment methods and clinical outcomes of patients with HSOS were analyzed. Results The incidence of HSOS after liver transplantation was 0.8%(2/239), and the median time of onset was 4.5(1.7, 9.0) months after liver transplantation. The clinical manifestations of HSOS mainly included abdominal distension, ascites, hepatomegaly, increased bilirubin, and renal insufficiency in partial cases. Enhanced abdominal CT scan of 4 patients with HSOS showed uneven spot-like enhancement and the liver histopathological examination mainly showed the signs of hepatic sinusoidal dilatation complicated with congestion. Four patients were administered with an adjusted regime of immunosuppressant by replacing tacrolimus (Tac) with ciclosporin and adding anticoagulant therapy with warfarin. One patient received transjugular intrahepatic portosystemic shunt (TIPS). After treatment, the symptoms of 3 patients were completely relieved, and 1 patient died. One of the 3 surviving patients died from pulmonary infection and gastrointestinal bleeding. Conclusions HSOS is a rare and fatal complication after liver transplantation. Timely diagnosis and treatment can avoid the incidence of graft failure and improve clinical prognosis of the patients.

Kinetic study of pyrrolizidine alkaloid-derived pyrrole-protein adducts in rats after intragastric administration of Gynura japonica / 药学学报

Recently, hepatic sinusoidal obstruction syndrome (HSOS) induced by misuse of Gynura japonica has increased and gained global attention. Large amounts of pyrrolizidine alkaloids (PAs) are present in G. japonica; these PAs are metabolically activated to generate pyrrole-protein adducts (PPAs). In this study, male SD rats were treated orally with a single dose of G. japonica extract (GJE) at 0.062 5, 0.25, 0.5, 1, and 2 g·kg-1. Blood was collected from the orbital venous plexus at 2, 12, 24 and 48 h, and at 48 h after treatment the rats were anesthetized with isoflurane and livers were collected for hematoxylin & eosin staining. The kinetics of PPAs at different doses were studied at 10, 20, 30 min, 1, 2, 4, 6, 12, 24 h, and 48 h, after a single gavage of GJE. The experimental scheme was approved by the ethics committee of animal experiments of Shanghai University of Traditional Chinese Medicine (PZSHUTCM190912019). The concentration of PPAs in serum was determined by liquid chromatography-mass spectrometry (LC-MS). Kinetic data were processed by using the non-compartmental pharmacokinetics data analysis software program PK solutions 2™. The results demonstrate that the concentration of PPAs increased with the dose of GJE and positively correlated with the severity of liver injury. The elimination rate of PPAs in rats was significantly prolonged at higher doses. The level of PPAs and their clearance rate may serve as useful references for the detoxification of PAs-induced injuries.

The clinical thinking of diagnosis and treatment of cryptogenic cirrhosis / 医学研究生学报

Cryptogenic cirrhosis (CC), cirrhosis of unknown cause, is common in clinic. With the improvement of the level of diagnosis and the diversification of the diagnosis and treatment, the incidence of CC is gradually declining. In the process of diagnosis and treatment, perfect clinical thinking can help clinicians to analyze and evaluate the existing clinical data, and it is expected to further improve the diagnostic rate of CC. In this paper, the clinical thinking of CC diagnosis and treatment is expounded from the aspects of disease spectrum thinking, anatomy thinking and macroscopic micro thinking.

Clinical characteristics of 115 cases of gynura segetum induced hepatic sinusoidal obstruction syndrome / 中华消化杂志

Objective To study the clinical characteristics of gynura segetum induced hepatic sinusoidal obstruction syndrome (HSOS).Methods From July 2008 to October 2016,a total of 115 cases of gynura segetum caused HSOS were retrospectively analyzed.The history of taking gynura segetum before disease onset was recorded and epidemiologic data of main clinical symptoms,clinical manifestations,laboratory examinations,imaging and pathological features were observed.Results Among the 115 cases of HSOS,there were 113 patients with abdominal pain,106 with anorexia and 42 with jaundice sclera.A total of 108 patients displayed increased serum total bilirubin,41 of them only with mildly increased total bilirubin.There were 29 patients with albumin lower than 30 g/L,64 patients with prolonged prothrombin time (PT) and PT of 11 patients was prolonged for more than three seconds.Meanwhile,31 patients were with prolonged activated partial prothrombin time (APTT).A total of 60 patients had low platelet count.And 92 patients underwent ultrasound examination,among them,71 patients had enlarged liver size,79 patients with uneven internal echo of liver,70 patients with ascites,14 patients with patchy low echo tissue around hepatic venous.A total of 60 patient accepted computed tomography (CT) examination,and all of them had ascites,14 patients with mildly enlarged spleen and eight patients with gastro-esophageal varices.The results of CT plain scan indicated hepatomegaly,decreased liver density,map-like changes of patchy low density in delayed phase,heterogeneous enhancement of liver parenchyma in arterial phase,compression and deformation of liver segment of inferior vena cava and halo sign around venous portal vein.The results of pathological examination demonstrated the widening of hepatic sinusoid with hemorrhage and congestion,destruction of liver plate in zone Ⅲ area.There were seven patients who received hepatic venous pressure gradient (HVPG) measurement which were all significantly increased.Conclusions The characteristics of patients with gynura segetum caused HSOS are abdominal pain,anorexia and jaundice;mildly increased serum total bilirubin and albumim liver enlargement,slow blood velocity of portal vein and splenic veim increased HVPG,hepatic sinus congestion and cell coagulation necrosis in zone Ⅲ area.

Hepatic Sinusoidal Obstruction Syndrome Caused by Herbal Medicine: CT and MRI Features

OBJECTIVE: To describe the CT and MRI features of hepatic sinusoidal obstruction syndrome (HSOS) caused by herbal medicine Gynura segetum. MATERIALS AND METHODS: The CT and MRI features of 16 consecutive Gynura segetum induced HSOS cases (12 men, 4 women) were analyzed. Eight patients had CT; three patients had MRI, and the remaining five patients had both CT and MRI examinations. Based on their clinical presentations and outcomes, the patients were classified into three categories: mild, moderate, and severe. The severity of the disease was also evaluated radiologically based on the abnormal hepatic patchy enhancement in post-contrast CT or MRI images. RESULTS: Ascites, patchy liver enhancement, and main right hepatic vein narrowing or occlusion were present in all 16 cases. Hepatomegaly and gallbladder wall thickening were present in 14 cases (87.5%, 14/16). Periportal high intensity on T2-weighted images was present in 6 cases (75%, 6/8). Normal liver parenchymal enhancement surrounding the main hepatic vein forming a clover-like sign was observed in 4 cases (25%, 4/16). The extent of patchy liver enhancement was statistically associated with clinical severity classification (kappa = 0.565). CONCLUSION: Ascites, patchy liver enhancement, and the main hepatic veins narrowing were the most frequent signs of herbal medicine induced HSOS. The grade of abnormal patchy liver enhancement was associated with the clinical severity.

6-Thioguanine-Induced Hepatic Sinusoidal Obstruction Syndrome in a Leukemic Child with TPMT Heterozygote / 임상소아혈액종양

Hepatic sinusoidal obstruction syndrome (hSOS) can be developed as a common complication after hematopoietic stem cell transplantation (HSCT), and rarely after 6-thioguanine-based chemotherapy without HSCT. A four-year-old boy with heterozygotic polymorphism for thiopurine methyltransferase (TPMT) developed hSOS after he received chemotherapy with cytarabine, cyclophosphamide, intrathecal methotrexate and 6-thioguanine (6-TG) as reconsolidation chemotherapy of acute lymphoblastic leukemia (ALL). He was treated with defibrotide, N-acetylcysteine, urusodeoxycholic acid, glutathione, and supportive care. He recovered completely in nine days without long-term complication, and completed chemotherapy with 6-mercaptopurine without severe complication. We report a case of hSOS developed in an ALL patient with TPMT heterozygote after 6-TG based reconsolidation chemotherapy.

6-Thioguanine-Induced Hepatic Sinusoidal Obstruction Syndrome in a Leukemic Child with TPMT Heterozygote / 임상소아혈액종양

Hepatic sinusoidal obstruction syndrome (hSOS) can be developed as a common complication after hematopoietic stem cell transplantation (HSCT), and rarely after 6-thioguanine-based chemotherapy without HSCT. A four-year-old boy with heterozygotic polymorphism for thiopurine methyltransferase (TPMT) developed hSOS after he received chemotherapy with cytarabine, cyclophosphamide, intrathecal methotrexate and 6-thioguanine (6-TG) as reconsolidation chemotherapy of acute lymphoblastic leukemia (ALL). He was treated with defibrotide, N-acetylcysteine, urusodeoxycholic acid, glutathione, and supportive care. He recovered completely in nine days without long-term complication, and completed chemotherapy with 6-mercaptopurine without severe complication. We report a case of hSOS developed in an ALL patient with TPMT heterozygote after 6-TG based reconsolidation chemotherapy.

Advances in hepatic sinusoidal obstruction syndrome after liver transplantation / 中华肝胆外科杂志

In liver transplantation,hepatic sinusoidal obstruction syndrome (HSOS) is rare,which results in misdiagnosis and mistreatment.The prognosis of HSOS after liver transplantation is related to the implementation of early specific treatment.No systematic review has been reported on HSOS after liver transplantation.To raise awareness of HSOS after liver transplantation,this review summarizes the aetiology,pathology,clinical manifestations,laboratory findings,imaging features,diagnosis,differential diagnosis,treatment and prognosis of the condition.