Gynura segetum induces hepatic sinusoidal obstruction syndrome in a child: A case report.

RATIONALE: Hepatic sinusoidal obstruction syndrome (HSOS), which includes hepatic stasis and portal hypertension, is a rare vascular disorder of the liver. It is often associated with hematopoietic stem cell transplantation. It is also possible to treat this disease using Chinese herbal medicines that contain pyrrolizidine alkaloids (PAs). This disease is extremely rare in children and poses a serious threat to their health. To our knowledge, this is the first case of HSOS in a child with PAs. PATIENT CONCERNS: We report a 4-year-old boy suffering from abdominal pain, hepatomegaly, massive ascites, elevated liver enzyme level, and severe portal hypertension as a result of the consumption of Gynura segetum (also known as Tusanqi in Chinese, a traditional herbal medicine containing PAs). DIAGNOSES: The child was finally diagnosed with PA-HSOS based on pathological diagnosis and imaging examination. INTERVENTION: With active symptomatic and supportive care and sequential anticoagulation therapy, the abdominal distension and liver function improved in the patient. OUTCOMES: The patient was eventually recovered. The levels of liver enzymes, hemoglobin, and bilirubin were normal, and the international normalized ratio fluctuated between 2.0 and 3.0 during 1-year follow-up after discharge. LESSONS: This case report emphasizes the prevention of Chinese herb-induced liver injury in children and the importance of active long-term sequential anticoagulant therapy to reduce the progressive damage of PA-HSOS in the liver.

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

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.

Timing and efficacy of transjugular intrahepatic portosystemic shunt in patients with pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

There is no specific treatment for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome (PA-HSOS). It is not clear when transjugular intrahepatic portosystemic shunt (TIPS) should be implemented in PA-HSOS patients. This study aimed to evaluate the timing of TIPS using total bilirubin (TBIL) as a measure, and to investigate efficacy of TIPS. We retrospectively analyzed the medical records of 10 PA-HSOS patients, among whom 4 patients had received TIPS (TIPS group), and the remaining patients were assigned to the internal medicine group. In the TIPS group, the TBIL level before TIPS was 84.4 ± 45.2 µmol/L (> 3 mg/dL), and TBIL levels were increased to different degrees after TIPS. With the extension of time, serum TBIL levels gradually decreased, and no liver failure occurred. With regards to the short-term outcomes, 3 patients recovered, 1 developed chronic illness and 0 died in the TIPS group. Moreover, 0 patients recovered, 5 developed chronic illness and 1 died in the internal medicine group. The rank sum test of group design revealed significant differences in clinical outcomes (P = 0.02). It was suggested that when the internal medicine effect of PA-HSOS patients is poor, TIPS should be considered, which is no trestricted to the limit of 3 mg/dL TBIL. It was also found TIPS effectively promote the recovery of liver function and reduce the occurrence of chronicity.

Spread of Jacobaea vulgaris and Occurrence of Pyrrolizidine Alkaloids in Regionally Produced Honeys from Northern Germany: Inter- and Intra-Site Variations and Risk Assessment for Special Consumer Groups.

Pyrrolizidine alkaloids (PA) and PA N-oxides (PANO) are secondary plant metabolites exhibiting genotoxic and carcinogenic properties. Apart from the roots and leaves, PA/PANO are particularly present in pollen and nectar. Therefore, the spread of Jacobaea vulgaris in certain regions of northern Germany has an impact on the safety of honey produced in that region. In this study, raw honey samples (n = 437) were collected from usually three individual beehives per site (n = 73) in the district of Ostholstein and analyzed for 25 PA/PANO. The results reveal mean levels of 8.4, 1.5, and 72.6 µg/kg and maximum levels of 111, 59.4, and 3313 µg/kg, depending on the season (summer 2015 and spring/summer 2016, respectively). As far as individual data are concerned, sites near areas with J. vulgaris growth did not necessarily result in high PA/PANO values. Furthermore, intra-site investigations revealed remarkable differences in PA/PANO levels of raw honey collected by different bee colonies at the same site. Consumption of these regionally produced honeys entails an increased exposure to PA/PANO, especially in children and high consumers. Margin of exposure values of <10,000 and an exceedance of the health-based guidance value highlight that regionally produced and marketed honey must be considered with care for a proper risk assessment and risk management.

Extracting and Analyzing Pyrrolizidine Alkaloids in Medicinal Plants: A Review.

Pyrrolizidine alkaloids (PAs) are distributed in plant families of Asteraceae, Boraginaceae, and Fabaceae and serve in the chemical defense mechanism against herbivores. However, they became a matter of concern due to their toxicity associated with the high risk of intake within herbal preparations, e.g., phytopharmaceutical formulations, medicinal teas, or other plant-derived drug products. In 1992, the German Federal Ministry of Health established the first limits of PA content for fourteen medicinal plants. Because of the toxic effects of PAs, the Federal Institute of Risk Assessment (BfR) established more stringent limits in 2011, whereby a daily intake <0.007 µg/kg body weight was recommended and valid until 2018. A threefold higher limit was then advised by BfR. To address consumer safety, there is the need for more efficient extraction procedures along with robust, selective, and sensitive analytical methods to address these concerns. With the increased prevalence of, e.g., phytopharmaceutical formulations, this timely review comprehensively focuses on the most relevant extraction and analysis strategies for each of those fourteen plant genera. While a variety of extraction procedures has been reported, differences in PA content of up to 1110 ppm (0.11% (w/w)) were obtained dependent on the nature of the solvent and the applied extraction technique. It is evident that the efficient extraction of PAs requires further improvements or at least standardization of the extraction conditions. Comparing the various analytical techniques applied regarding selectivity and sensitivity, LC-MS methods appear most suited. This review shows that both standardized extraction and sensitive determination of PAs is required for achieving appropriate safety levels concerning public health in future.

Quantitative Analysis of CT Images in Patients with Pyrrolizidine Alkaloid-Induced Sinusoidal Obstruction Syndrome.

This study evaluated hepatic lesion volumes on contrast-enhanced computed tomography (CT) images in patients with pyrrolizidine alkaloid-induced sinusoidal obstruction syndrome (PA-SOS) and the association of lesion volume with the clinical severity and prognosis of the disease. Twenty-five patients with PA-SOS were included in this study, and all patients were subjected to a complete CT imaging series. The imaging results were quantitatively analyzed by a threshold-based region growing algorithm. The liver volumes and hepatic lesion volumes of the patients were estimated. Based on clinical presentations, PA-SOS was classified into three categories: mild, moderate and severe. The associations of hepatic lesion volumes with liver function test parameters and the clinical severity and prognosis of the disease were analyzed. Based on estimations using the threshold-based region growing algorithm, hepatic lesion volumes in patients with mild PA-SOS were significantly lower than those in patients with moderate and severe PA-SOS (P < 0.05). The ratio of hepatic lesion volume to liver volume (Ratio) varied based on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum total bilirubine levels; clinical severity; and disease prognosis, and the differences were statistically significant (P < 0.05). In conclusion, the threshold-based region growing algorithm can be employed to quantitatively analyze enhanced CT images of PA-SOS patients. And the ratio of hepatic lesion volume to liver volume in patients with PA-SOS is associated with a more serious clinical course and a poorer outcome.

Gadoxetic Acid-Enhanced Hepatobiliary-Phase Magnetic Resonance Imaging for Pyrrolizidine Alkaloid-Induced Hepatic Sinusoidal Obstruction Syndrome and Association with Liver Function.

Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by pyrrolizidine alkaloids(PAs)-containing herbals. In this study, the aim of our study was to investigate the imaging features of PAs-induced HSOS on gadoxetic acid-enhanced magnetic resonance imaging (MRI), susceptibility-weighted imaging(SWI) and T2* weighted imaging (T2* WI). We analyzed medical records and MR images of 28 PAs-induced HSOS patients enrolled from Feb, 2013, to Apr, 2017. Abnormal liver function was observed in most of the PAs-induced HSOS patients. Heterogeneity of liver parenchyma in hepatobillary phase (HBP) of gadoxetic acid-enhanced MR scan was observed in 100% of the PAs-induced HSOS patients. Distributional patterns of heterogeneous hypointensity were multifocal distribution (mild) in 4 patients (14.29%), multifocal distribution (severe) in 15 cases (53.57%), and diffuse distribution in 9 patients (32.14%). Hypointense in SWI and T2*WI was observed in the patients of PAs-induced HSOS, and the distribution of hypointense in SWI and T2*WI was similar to that of portal-venous phase of MR scan. The severity of heterogeneous hypointensity scored by volume fraction in hepatobillary phase of gadoxetic acid-enhanced MRI was positively correlated with PT and INR, the severity of hypointensity in HBP was a risk factor of death events. In conclusion: Heterogenous hypointensity of liver parenchyma was an imaging sign of hepatobillary phase in gadoxetic acid-enhanced MRI; thus, it will provide evidences for the diagnosis of PA-induced HSOS.

A Balanced Risk-Benefit Analysis to Determine Human Risks Associated with Pyrrolizidine Alkaloids (PA)-The Case of Herbal Medicinal Products Containing St. John's Wort Extracts (SJW).

OBJECTIVES: Pyrrolizidine alkaloids (PA) exist ubiquitously in our environment. More than 6000 plants, about 3% of the world’s flowering plants, are known to synthesize PA. As a consequence, many herbal ingredients, including St. John’s wort (SJW), are contaminated with PA that can possess acute and subchronic toxic effects as well as mutagenic and genotoxic properties. Therefore, the possible benefits of SJW as an herbal remedy against depression need to be weighed against the possible risks of unwanted PA intake. METHODS: We searched the literature regarding the current knowledge on PA and evaluated the evidence on the antidepressant effects of quantified SJW extract based on a Cochrane Review and the current practice guidelines on depression. Risks are depicted in form of a risk ladder and benefits in form of an icon array. RESULTS: Evidence from clinical studies indicates that quantified SJW extract is an effective treatment option for mild to moderate depression with fewer side effects than conventional antidepressants. Health statistics from different countries do not quantify cases of death caused by PA intake. However, deaths due to suicide, often triggered by depression, are common (11 in 1000 in Germany in 2015) and rank between fatalities due to liver diseases (16 in 1000) and household accidents (10 in 1000). CONCLUSIONS: Quantified SJW extract is a safe and effective treatment option, and its potential of treating depression outweighs the (hypothetical) risk of unwanted PA intake.

Toxic pyrrolizidine alkaloids provide a warning sign to overuse of the ethnomedicine Arnebia benthamii.

ETHNOPHARMACOLOGICAL RELEVANCE: From early times man has used medicinal plants for the treatment of various ailments and basic health care needs. The use of herbal medicines has increased day by day and with this, so do reports of adverse events, poisoning, and suspected toxicity. Similarly, the indigenous communities of Neelum Valley in Azad Kashmir commonly use Arnebia benthamii (Wall. ex G.Don) I.M.Johnst. for medicinal purposes to treat various human aliments. Besides their medicinal uses, it also contains hepatotoxic pyrrolizidine alkaloids (PAs). AIM OF THE STUDY: This explorative study underscores two major aspects about this herbal medicine. Firstly we aimed to document the traditional therapeutic uses of Arnebia benthamii in Neelum Valley, Azad Kashmir. Secondly, to determine the presence or absence of hepatotoxic pyrrolizidine alkaloids and if they are within the suggested limit for the use of herbs in excess. MATERIALS AND METHODS: Interviews, group discussions, and inquiries were carried out from July to September 2016 with local indigenous and elder people. In the laboratory, the plant was investigated for pyrrolizidine alkaloids by using high performance liquid chromatography (HPLC). RESULTS: A total of 30 respondents were interviewed. They explained the preferred preparation, parts used, and treatment indications. Treatment of fever along with kidney and liver problems are the three principle uses. Among the different parts of Arnebia benthamii, 43% respondents preferred aerial parts for the herbal formulation, followed by whole plants, and leaves. Decoction was the major mode of preparation and all herbal preparations were administrated orally. This study reports, for the first time according to our literature review, a study of Arnebia benthamii with regard to PA determination. By using column Zorbax SB-Aq and acetonitrile-water gradient as the mobile phase, HPLC results showed that the aerial parts of the plant were PA positive, and (1) Europine, Heliotrine (2), Lycopsamine (3), and Echimidine (4) were identified. CONCLUSIONS: This study has revealed two new findings of significance to herbal medicine producers, practitioners, and consumers of Arnebia benthamii First, local knowledge regarding the medicinal uses of Arnebia benthamii were documented in five sites of Neelum Valley, Azad Kashmir. The use of this plant by a large part of the population in the study area shows the importance for their therapeutic benefits. Unfortunately, the second finding of this study shows that Arnebia benthamii contains hepatotoxic PAs. Hence, we advised to the government regulatory authorities and non-governmental organizations that use of this plant as herbal medicine should be excluded before more accurate quality control tests.

Enfermedad venooclusiva hepática inducida por hierbas medicinales chinas / Hepatic veno-occlusive disease induced by Chinese medicinal herbs

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Hepatic veno-occlusive disease induced by Chinese medicinal herbs.

The potential hepatotoxic effects of products containing medicinal herbs, which are increasingly used without adequate control by health authorities, is well known. We report a case of toxic hepatic veno-occlusive disease (HVOD) presumably associated with the use of such herbal remedies.

A Balanced Risk-Benefit Analysis to Determine Human Risks Associated with Pyrrolizidine Alkaloids (PA)-The Case of Tea and Herbal Infusions.

Humans are exposed to pyrrolizidine alkaloids (PA) through different sources, mainly from contaminated foodstuff. Teas and herbal infusions (T&HI) can be contaminated by PA producing weed. PA can possess toxic, mutagenic, genotoxic, and carcinogenic properties. Thus, possible health risks for the general population are under debate. There is a strong safety record for T&HI and additionally epidemiological evidence for the preventive effects of regular tea consumption on cardiovascular events and certain types of cancer. There is no epidemiological evidence, however, for human risks of regular low dose PA exposure. Recommended regulatory PA-threshold values are based on experimental data only, accepting big uncertainties. If a general risk exists through PA contaminated T&HI, it must be small compared to other frequently accepted risks of daily living and the proven health effects of T&HI. Decision making should be based on a balanced riskbenefit analysis. Based on analyses of the scientific data currently available, it is concluded that the benefits of drinking T&HI clearly outweigh the negligible health risk of possible PA contamination. At the same time, manufacturers must continue their efforts to secure good product quality and to be transparent on their measures of quality control and risk communication.

First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans.

Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N-oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N-oxides remains unclear. The current study unequivocally identified PA N-oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N-oxides were recorded to induce HSOS in human. PA N-oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 µmol PA N-oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N-oxide (55 µmol/kg) on rats revealed the toxic mechanism that PA N-oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N-oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N-oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N-oxides present in herbs and foods should be regulated and controlled in use.

Diagnostic performance of Contrast-enhanced CT in Pyrrolizidine Alkaloids-induced Hepatic Sinusoidal Obstructive Syndrome.

Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by pyrrolizidine alkaloids(PAs)-containing herbals. Since PAs exposure is obscure and clinical presentation of HSOS is unspecific, it is challenge to establish the diagnosis of PAs-induced HSOS. Gynura segetum is one of the most wide-use herbals containing PAs. The aim of our study is to describe the features of contrast-enhanced computed tomography (CT) in gynura segetum-induced HSOS, and then determine diagnostic performance of radiological signs. We retrospectively analyzed medical records and CT images of HSOS patients (71 cases) and the controls (222 cases) enrolled from January 1, 2008, to Oct 31, 2015. The common findings of contrast CT in PAs-induced HSOS included: ascites (100%), hepatomegaly (78.87%), gallbladder wall thickening (86.96%), pleural effusion (70.42%), hepatic vein narrowing (87.32%), patchy liver enhancement (92.96%), and heterogeneous hypoattenuation (100%); of these signs, patchy enhancement and heterogeneous hypoattenuation were valuable features. Then, the result of diagnostic performance demonstrated that contrast CT possessed better performance in diagnosing PAs-induced HSOS compared with various parameters of Seattle criteria. In conclusion, the patients with PAs-induced HSOS display distinct radiologic features at CT-scan, which reveals that contrast-enhanced CT provides an effective noninvasive method for diagnosing PAs-induced HSOS.

Risk assessment on the use of herbal medicinal products containing pyrrolizidine alkaloids.

Pyrrolizidine alkaloids (PA) are common plantal toxins directed against insect herbivores. Unsaturated PAs are known to be hepatotoxic. Many of the PAs are in addition mutagenic and some may possibly be carcinogenic for humans. The risk of an exposure to PAs associated with their occurrence in herbal medicinal products and in foodstuff is under current discussion. The present risk assessment for herbal medicinal products containing PAs is based on a margin of safety derivation for foodstuff indicating that a life-long exposure to maximally 0.007 µg/kg bw/day is not expected to be associated with safety concerns. This approach offers a possibility to estimate the potential risk of PA-containing herbal medicinal products irrespective of the route of administration. It assumes PA levels in the final herbal medicinal product below 0.01 ppm and considers for dermal administration a 100% skin penetration of the PAs reflecting a worst-case scenario. As a result, the calculated margins of safety show a potential exposure using herbal medicinal products 70-, 45.5-, and 19.3-fold lower on a one-day base and 608-, 396-, and 168- fold lower on a one-year base for adults, children aged 12 years, and children aged 4 years, respectively, than the thresholds considered acceptable for foodstuff.

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.

Tusanqi and hepatic sinusoidal obstruction syndrome.

Hepatic sinusoidal obstruction syndrome (HSOS), characterized by hepatomegaly, ascites and hyperbilirubinemia, is caused by toxic injury to hepatic sinusoidal endothelial cells. One major etiology of HSOS in China is the intake of products containing pyrrolizidine alkaloids (PA) such as Tusanqi. The manifestations of patients with HSOS are usually non-specific, presenting with abnormal liver function and portal hypertension. Diagnosis of the disease depends mostly on liver histopathology when clinical and imaging data are not sufficient. A history of Tusanqi intake is mostly important for the diagnosis. Due to a lack of effective, evidence-based treatments for HSOS, avoiding the mistaken use of PA-containing products including Tusanqi is important for the prevention of HSOS.

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.

Budd-Chiari syndrome secondary to toxic pyrrolizidine alkaloid exposure.

In this report, we describe a case of pyrrolizidine alkaloid-related Budd-Chiari syndrome in Hong Kong. A 10-month-old boy presented with ascites, right pleural effusion, and hepatomegaly after consumption of herbal drinks for 3 months. His clinical (including imaging) features were compatible with Budd-Chiari syndrome. Budd-Chiari syndrome is a rare disease entity in paediatric patients. In our case, extensive workup performed to look for the underlying cause of Budd-Chiari syndrome was unrevealing, except for toxic pyrrolizidine alkaloid exposure in his herbal drinks.

Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.