scholarly journals Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update

2021 ◽  
Vol 22 (19) ◽  
pp. 10419
Author(s):  
Rolf Teschke ◽  
Noudeng Vongdala ◽  
Nguyen Van Quan ◽  
Tran Ngoc Quy ◽  
Tran Dang Xuan
Keyword(s):  
Double Bond ◽  
Pyrrolizidine Alkaloids ◽  
Plasma Membranes ◽  
Assessment Method ◽  
Sinusoidal Obstruction Syndrome ◽  
Liver Sinusoidal Endothelial Cells ◽  
Diagnostic Biomarkers ◽  
Hepatic Sinusoidal Obstruction Syndrome ◽  
Life Threatening ◽  
Heterocyclic Structure

Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.

scholarly journals Blood microRNA Signatures Serve as Potential Diagnostic Biomarkers for Hepatic Sinusoidal Obstruction Syndrome Caused by Gynura japonica Containing Pyrrolizidine Alkaloids

2021 ◽  
Vol 12 ◽  
Author(s):  
Xunjiang Wang ◽  
Wei Zhang ◽  
Yongfeng Yang ◽  
Yiran Chen ◽  
Yuzheng Zhuge ◽  
...  
Keyword(s):  
Pyrrolizidine Alkaloids ◽  
Validation Cohort ◽  
Sinusoidal Obstruction Syndrome ◽  
Operating Characteristics ◽  
Diagnostic Biomarkers ◽  
Hepatic Sinusoidal Obstruction Syndrome ◽  
Healthy Donors ◽  
Receiver Operating Characteristics Curve ◽  
Differentially Expressed Mirnas ◽  
Potential Biomarkers

Background and Aims: The Gynura japonica-induced hepatic sinusoidal obstruction syndrome (HSOS) is closely related to pyrrolizidine alkaloids (PAs), and its prevalence has been increasing worldwide in recent years. However, no effective therapy for PA-induced HSOS in clinics is available, partially due to the failure of quick diagnosis. This study aims to identify blood microRNA (miRNA) signatures as potential biomarkers for PA-induced HSOS in clinics.Methods: The microarray-based miRNA profiling was performed on blood samples of the discovery cohort, which consisted of nine patients with HSOS and nine healthy donors. Differentially expressed miRNAs were further confirmed using a validation cohort, which consisted of 20 independent patients with HSOS. In addition, the rat model was established through the oral administration of the total alkaloid extract from G. japonica to investigate the association of miRNA biomarkers with the progression of HSOS. Bioinformatic analyses, including GO and KEGG enrichment, receiver operating characteristics curve, and correlation analyses were conducted to evaluate the accuracy of the potential miRNA biomarkers.Results: Three miRNAs, namely miR-148a-3p, miR-362-5p, and miR-194-5p, were overexpressed in patients and rats with PA-induced HSOS. These miRNAs were positively related to the severity of liver injury and displayed considerable diagnostic accuracy for patients with HSOS with areas under the curve over 0.87.Conclusion: In summary, this study demonstrated that three miRNAs, hsa-miR-148a-3p, hsa-miR-362-5p, and hsa-miR-194-5p, might serve as potential biomarkers for PA-induced HSOS in clinics.

scholarly journals Prognostic risk factors for patients with hepatic sinusoidal obstruction syndrome caused by pyrrolizidine alkaloids

2021 ◽  
Author(s):  
Xiaofei Du ◽  
Zhenli Liu ◽  
Haibin Yu ◽  
Yu Wang ◽  
Zhengsheng zou ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Pyrrolizidine Alkaloids ◽  
Survival Rates ◽  
Anticoagulation Therapy ◽  
Bleeding Complications ◽  
Sinusoidal Obstruction Syndrome ◽  
Hepatic Sinusoidal Obstruction Syndrome ◽  
Intrahepatic Portosystemic Shunt ◽  
Class C ◽  
Prognostic Risk Factors

Abstract Background Pyrrolizidine alkaloids induced hepatic sinusoidal obstruction syndrome (PA-HSOS) often occurs after consuming herbs and a dietary supplement containing the plant Tu-San-Qi. Limited data exists to identify patients with fatal outcomes for early interventions. We aimed to analyze the predictors for 3-month survival. Methods We retrospectively enrolled PA-HSOS patients in 5 hospitals and extracted data from the onset of PA-HSOS to 36 months. Outcome measurements were 3-month and 36-month survival rates, baseline prognostic predictors for survival, and the effects of anticoagulant therapy. Results Among 49 enrollees, the median age was 60 and 49% male. At the onset of PA-HSOS, patients with Child-Turcotte-Pugh (CTP) class of A, B, or C were 8.2% (4/49), 42.8% (21/49), and 49.0% (24/49), respectively. None of them received a transjugular intrahepatic portosystemic shunt or a liver transplant. The 3-month and 36-month survival rates were 86% and 75%, respectively. Compared to the CTP class A or B, class C at baseline independently predicted lower survival rates at both 3 and 36 months. However, anticoagulation therapy treatment within the first three months independently predicted significantly higher survival rates at both time-points. The greatest benefit of anticoagulants (HR=2.54) was in patients with CTP class C compared with the survival rates with those without treatment (93% vs. 40%, p=0.009). There were no bleeding complications reported in patients treated with the anticoagulant. Conclusion We observed a 3-month survival rate of 86% in PA-HSOS patients, CTP class C and receiving anticoagulant therapy were the independent predictors associated with the survival.

scholarly journals Endothelial cell dysfunction: a key determinant for the outcome of allogeneic stem cell transplantation

2021 ◽  
Author(s):  
Thomas Luft ◽  
Peter Dreger ◽  
Aleksandar Radujkovic
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Current Status ◽  
Sinusoidal Obstruction Syndrome ◽  
Hematopoietic Stem ◽  
Cell Dysfunction ◽  
Management Of Complications ◽  
Life Threatening

AbstractAllogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.

Sign in / Sign up

Export Citation Format

Share Document