Clinical Efficacy and Safety of Anticoagulation Therapy for Pyrrolizidine Alkaloids-Induced Hepatic Sinusoidal Obstruction Syndrome: A Retrospective Multicenter Cohort Study

Peng, Chunyan; Zhang, Xiaofeng; Zhang, Feng; Liu, Longgen; Shao, Youlin; Xiang, Xiaoxing; Zhang, Wei; Xiao, Jiangqiang; Wang, Yi; Zhou, Bin; Yin, Qin; Song, Yufang; Mo, Zhe; Zou, Xiaoping; Zhang, Ming; Zhuge, Yuzheng

doi:10.2139/ssrn.3437800

Cited by 7 publications

(28 citation statements)

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“…Apart from the cessation of PA exposure, symptomatic management of the ascites is the primary therapeutic goal, achieved by restriction of fluid and salt (sodium) intake, a diet rich in proteins, and drug treatment with spironolactone [ 6 ]. For refractory ascites, therapeutic options in selected patients may include anticoagulant therapy [ 6 , 238 , 239 ], transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation, but positive data derived from RCTs are limited, in part controversially discussed, and require case-by-case decisions due to the lack of an established standard therapy [ 6 ]. Independent prognostic factors for patients with PA-HSOS are serum albumin, serum urea, and severity grading, facilitating early intervention in patients at increased risks [ 240 ].…”

Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

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

Teschke

Noudeng

Quan

et al. 2021

IJMS

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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.

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Section: Clinical Specifics Of Hsos Caused By 12-unsaturated Pasmentioning

confidence: 99%

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

Teschke

Noudeng

Quan

et al. 2021

IJMS

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“…The patients who had a platelet count of less than 50*10^9/L at baseline or who were hypersensitive to low-molecularweight heparin were given warfarin alone. The starting dose for warfarin monotherapy was 1.5 mg daily and was subsequently adjusted to obtain a target INR of 2.0-3.0 9 . If the PA-HSOS patients did not respond to the initial anticoagulant therapy, more aggressive treatments such as TIPS were then considered.…”

Section: Treatment Regimensmentioning

confidence: 99%

“…In 2017, the rst diagnostic criteria and treatment strategy for PA-HSOS were proposed 7 . Anticoagulation-transjugular intrahepatic portosystemic shunt (TIPS) stepwise therapy (anticoagulation rst, if no response, step-up to TIPS therapy) is recommended, and this has an increased survival up to 91% 1,[8][9][10][11][12] . However, the exact mechanism of this treatment modality is unclear.…”

Section: Introductionmentioning

confidence: 99%

The value of hepatic venous pressure gradient in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome

Cai

Zhang

et al. 2022

Preprint

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Background Pyrrolidine alkaloid‑induced hepatic sinusoidal obstruction syndrome (PA-HSOS) is a drug-induced liver injury characterized by sudden and rapidly progressive portal hypertension. Hepatic venous pressure gradient (HVPG) is the gold standard for the diagnosis of sinus hypertension, at least in viral and alcoholic liver disease, while its role in evaluating disease severity and treatment choice and predicting prognosis in patients with PA-HSOS needs further verification. The aim of this study was to investigate the clinical value of HVPG in patients with PA-HSOS. Methods Patients who were diagnosed with PA-HSOS according to the “Nanjing criteria” and received HVPG measurements in our hospital between January 2016 and April 2020 were reviewed retrospectively. Next, the predictive efficacy of HVPG in initial anticoagulant therapy, the prognostic survival of patients in different HVPG groups, the relationship between HVPG and the Drum Tower Severity Scoring (DTSS), the correlation between HVPG and pathological data were all evaluated. Results A total of 76 PA-HSOS patients were included in the study. Multivariate logistic regression analysis identified HVPG as independently associated with nonresponse to initial anticoagulation (95% CI: 1.006-1.413, P=0.043). The receiver operating characteristic curve (ROC) identified a cutoff value of 20.165 mmHg (sensitivity: 0.744, specificity: 0.697) for predicting nonresponse to initial anticoagulation, and the area under the curve (AUC) was 0.741 (95% CI: 0.626-0.857, P<0.001). When HVPG>20.165 mmHg was combined with serum total bilirubin (STB), heart rate (HR) and blood urea nitrogen (BUN) for modeling, the AUC was 0.881 (P<0.001). Seventy-six patients were divided into two groups according to whether HVPG was greater than 20.165 mmHg, and the patients in the high HVPG group (HVPG＞20.165 mmHg) had a significantly worse prognostic survival than the patients in the low HVPG group (HVPG＜20.165 mmHg) (P=0.022, χ2=5.285). Additionally, there was a linear correlation between HVPG and the area of sinusoidal bleeding in 76 patients (P=0.008, R=0.343). Furthermore, after excluding the patients with an onset time of more than 1 month, HVPG improved the efficacy in predicting nonresponse to anticoagulant therapy (AUC=0.789, 95% CI: 0.654-0.924, P=0.001), and the linear relationship between HVPG and bleeding area in the sinusoids was enhanced (P=0.001, R=0.499). In addition, a linear relationship between HVPG and DTSS emerged (P<0.001, R=0.522). Conclusions HVPG can assist in predicting the outcome of anticoagulant therapy and prognosis in patients with PA-HSOS, and this prediction is more accurate for patients within one month of disease onset.

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“…In addition, other PAs are suspected carcinogens that increase the risk of tumor formation and cause genotoxicity, probably by forming DNA adducts. Several intoxication and lethal cases through food ingestion or herbal medicines containing PAs have been reported [6–8]. The toxicity associated with PAs has raised great concern in human health when consumed at high levels.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of eight pyrrolizidine alkaloids in various parts of Eupatorium lindleyanum by ultra high performance liquid chromatography tandem mass spectrometry and risk assessments based on a real‐life exposure scenario

Zan

et al. 2021

J of Separation Science

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Pyrrolizidine alkaloids are toxins having hepatotoxic and carcinogenic effects on human health. A ultra high performance liquid chromatography tandem mass spectrometry technique was developed for the first time for the simultaneous determination of eight pyrrolizidine alkaloids, including four diastereoisomers (intermedine, lycopsamine, rinderine, and echinatine) and their respective N‐oxide forms, in different parts of Eupatorium lindleyanum. The risk assessment method for pyrrolizidine alkaloids in Eupatorium lindleyanum was explored using the margin of exposure strategy for the first time based on a real‐life exposure scenario. Differences were found in all eight pyrrolizidine alkaloids in various parts of Eupatorium lindleyanum. Besides, the total levels of pyrrolizidine alkaloids in Eupatorium lindleyanum followed the order of root > flower > stem > leaf. Moreover, the risk assessment data revealed that the deleterious effects on human health were unlikely at exposure times of less than 200, 37, and 12 days during the lifetimes of Eupatorium lindleyanum leaves, stems, and flowers, respectively. This study reported both the contents of and risk associated with Eupatorium lindleyanum pyrrolizidine alkaloids. The comprehensive application of the novel ultra high performance liquid chromatography tandem mass spectrometry technique alongside the risk assessment approach provided a scientific basis for quality evaluation and rational utilization of toxic pyrrolizidine alkaloids in Eupatorium lindleyanum to improve public health safety.

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Clinical Efficacy and Safety of Anticoagulation Therapy for Pyrrolizidine Alkaloids-Induced Hepatic Sinusoidal Obstruction Syndrome: A Retrospective Multicenter Cohort Study

Cited by 7 publications

References 0 publications

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

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

The value of hepatic venous pressure gradient in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome

Simultaneous determination of eight pyrrolizidine alkaloids in various parts of Eupatorium lindleyanum by ultra high performance liquid chromatography tandem mass spectrometry and risk assessments based on a real‐life exposure scenario

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