|
1
|
Xu XT, Wang BH, Wang Q, Guo YJ, Zhang YN, Chen XL, Fang YF, Wang K, Guo WH, Wen ZZ. Idiopathic hypereosinophilic syndrome with hepatic sinusoidal obstruction syndrome: A case report and literature review. World J Gastrointest Surg 2023; 15:1532-1541. [PMID: 37555104 PMCID: PMC10405125 DOI: 10.4240/wjgs.v15.i7.1532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/17/2023] [Accepted: 05/17/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Hypereosinophilic syndrome (HES) is classified as primary, secondary or idiopathic. Idiopathic HES (IHES) has a variable clinical presentation and may involve multiple organs causing severe damage. Hepatic sinusoidal obstruction syndrome (HSOS) is characterized by damage to the endothelial cells of the hepatic sinusoids of the hepatic venules, with occlusion of the hepatic venules, and hepatocyte necrosis. We report a case of IHES with HSOS of uncertain etiology. CASE SUMMARY A 70-year-old male patient was admitted to our hospital with pruritus and a rash on the extremities for > 5 mo. He had previously undergone antiallergic treatment and herbal therapy in the local hospital, but the symptoms recurred. Relevant examinations were completed after admission. Bone marrow aspiration biopsy showed a significantly higher percentage of eosinophils (23%) with approximately normal morphology. Ultrasound-guided hepatic aspiration biopsy indicated HSOS. Contrast-enhanced computed tomography (CT) of the upper abdomen showed hepatic venule congestion with hydrothorax and ascites. The patient was initially diagnosed with IHES and hepatic venule occlusion. Prednisone, low molecular weight heparin and ursodeoxycholic acid were given for treatment, followed by discontinuation of low molecular weight heparin due to ecchymosis. Routine blood tests, biochemical tests, and imaging such as enhanced CT of the upper abdomen and pelvis were reviewed regularly. CONCLUSION Hypereosinophilia may play a facilitating role in the occurrence and development of HSOS.
Collapse
Affiliation(s)
- Xu-Tao Xu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Bing-Hong Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Qiang Wang
- Department of Hepatopancreatobiliary Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Yang-Jie Guo
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yu-Ning Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Xiao-Li Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yan-Fei Fang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Kan Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Wen-Hao Guo
- Department of Pathology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Zhen-Zhen Wen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| |
Collapse
|
|
2
|
Ebmeyer J, Rasinger JD, Hengstler JG, Schaudien D, Creutzenberg O, Lampen A, Braeuning A, Hessel-Pras S. Hepatotoxic pyrrolizidine alkaloids induce DNA damage response in rat liver in a 28-day feeding study. Arch Toxicol 2020; 94:1739-1751. [PMID: 32419051 PMCID: PMC7261731 DOI: 10.1007/s00204-020-02779-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/05/2020] [Indexed: 11/29/2022]
Abstract
Pyrrolizidine alkaloids (PA) are secondary plant metabolites that occur as food and feed contaminants. Acute and subacute PA poisoning can lead to severe liver damage in humans and animals, comprising liver pain, hepatomegaly and the development of ascites due to occlusion of the hepatic sinusoids (veno-occlusive disease). Chronic exposure to low levels of PA can induce liver cirrhosis and liver cancer. However, it is not well understood which transcriptional changes are induced by PA and whether all hepatotoxic PA, regardless of their structure, induce similar responses. Therefore, a 28-day subacute rat feeding study was performed with six structurally different PA heliotrine, echimidine, lasiocarpine, senecionine, senkirkine, and platyphylline, administered at not acutely toxic doses from 0.1 to 3.3 mg/kg body weight. This dose range is relevant for humans, since consumption of contaminated tea may result in doses of ~ 8 µg/kg in adults and cases of PA ingestion by contaminated food was reported for infants with doses up to 3 mg/kg body weight. ALT and AST were not increased in all treatment groups. Whole-genome microarray analyses revealed pronounced effects on gene expression in the high-dose treatment groups resulting in a set of 36 commonly regulated genes. However, platyphylline, the only 1,2-saturated and, therefore, presumably non-hepatotoxic PA, did not induce significant expression changes. Biological functions identified to be affected by high-dose treatments (3.3 mg/kg body weight) comprise cell-cycle regulation associated with DNA damage response. These functions were found to be affected by all analyzed 1,2-unsaturated PA. In conclusion, 1,2-unsaturated hepatotoxic PA induced cell cycle regulation processes associated with DNA damage response. Similar effects were observed for all hepatotoxic PA. Effects were observed in a dose range inducing no histopathological alterations and no increase in liver enzymes. Therefore, transcriptomics studies identified changes in expression of genes known to be involved in response to genotoxic compounds at PA doses relevant to humans under worst case exposure scenarios.
Collapse
Affiliation(s)
- Johanna Ebmeyer
- German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | | | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Dirk Schaudien
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Straße 1, 30625, Hanover, Germany
| | - Otto Creutzenberg
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Straße 1, 30625, Hanover, Germany
| | - Alfonso Lampen
- German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Albert Braeuning
- German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Stefanie Hessel-Pras
- German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
| |
Collapse
|
|
3
|
Hessel-Pras S, Braeuning A, Guenther G, Adawy A, Enge AM, Ebmeyer J, Henderson CJ, Hengstler JG, Lampen A, Reif R. The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice. Arch Toxicol 2020; 94:219-229. [PMID: 31606820 DOI: 10.1007/s00204-019-02582-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/18/2019] [Indexed: 02/07/2023]
Abstract
Pyrrolizidine alkaloids (PAs) are widely occurring phytotoxins which can induce severe liver damage in humans and other mammalian species by mechanisms that are not fully understood. Therefore, we investigated the development of PA hepatotoxicity in vivo, using an acutely toxic dose of the PA senecionine in mice, in combination with intravital two-photon microscopy, histology, clinical chemistry, and in vitro experiments with primary mouse hepatocytes and liver sinusoidal endothelial cells (LSECs). We observed pericentral LSEC necrosis together with elevated sinusoidal marker proteins in the serum of senecionine-treated mice and increased sinusoidal platelet aggregation in the damaged tissue regions. In vitro experiments showed no cytotoxicity to freshly isolated LSECs up to 500 µM senecionine. However, metabolic activation of senecionine by preincubation with primary mouse hepatocytes increased the cytotoxicity to cultivated LSECs with an EC50 of approximately 22 µM. The cytochrome P450 (CYP)-dependency of senecionine bioactivation was confirmed in CYP reductase-deficient mice where no PA-induced hepatotoxicity was observed. Therefore, toxic metabolites of senecionine are generated by hepatic CYPs, and may be partially released from hepatocytes leading to destruction of LSECs in the pericentral region of the liver lobules. Analysis of hepatic bile salt transport by intravital two-photon imaging revealed a delayed uptake of a fluorescent bile salt analogue from the hepatic sinusoids into hepatocytes and delayed elimination. This was accompanied by transcriptional deregulation of hepatic bile salt transporters like Abcb11 or Abcc1. In conclusion, senecionine destroys LSECs although the toxic metabolite is formed in a CYP-dependent manner in the adjacent pericentral hepatocytes.
Collapse
Affiliation(s)
- Stefanie Hessel-Pras
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany.
| | - Albert Braeuning
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Georgia Guenther
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| | - Alshaimaa Adawy
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| | - Anne-Margarethe Enge
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Johanna Ebmeyer
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Colin J Henderson
- Systems Medicine, Jacqui Wood Cancer Centre, University of Dundee, School of Medicine, James Arrott Drive, Ninewells Hospital, Dundee, UK
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| | - Alfonso Lampen
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Raymond Reif
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| |
Collapse
|
|
4
|
Waizenegger J, Braeuning A, Templin M, Lampen A, Hessel-Pras S. Structure-dependent induction of apoptosis by hepatotoxic pyrrolizidine alkaloids in the human hepatoma cell line HepaRG: Single versus repeated exposure. Food Chem Toxicol 2018; 114:215-226. [PMID: 29458164 DOI: 10.1016/j.fct.2018.02.036] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/12/2018] [Accepted: 02/15/2018] [Indexed: 11/28/2022]
Abstract
Pyrrolizidine alkaloids (PA) are secondary plant compounds. PA intoxication in humans causes severe acute and chronic hepatotoxicity. However, the molecular mechanisms of PA hepatotoxicity in humans are not well understood yet. Therefore, we investigated cell death parameters in human HepaRG cells following either single (24 h) or repeated dose treatment (14 d) with structurally different PA of the retronecine (echimidine, senecionine), heliotridine (heliotrine), and otonecine type (senkirkine). After 24 h of exposure only retronecine-type PA were cytotoxic in HepaRG cells and induced apoptosis indicated by a loss of membrane asymmetry, disruption of the mitochondrial membrane potential, and increased pro-caspase and PARP cleavage. In contrast, after 14 d all four PA exerted the aforementioned effects. Furthermore, the apoptotic events caspase 3, 8 and 9 activation as well as nuclear condensation and DNA fragmentation were only detected for the retronecine-type PA after single exposure (6 h). Overall, our studies revealed a time- and structure-dependent apoptosis after PA exposure, suggesting that retronecine-type PA seem to be more potent apoptosis inducers than heliotridine- or otonecine-type PA. Furthermore, our results suggest that PA-induced apoptosis in HepaRG cells occur most probably by involving both, the extrinsic death receptor pathway as well as the intrinsic mitochondrial pathway.
Collapse
Affiliation(s)
- Julia Waizenegger
- German Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany
| | - Albert Braeuning
- German Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany
| | - Markus Templin
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstraße 55, 72770 Reutlingen, Germany
| | - Alfonso Lampen
- German Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany
| | - Stefanie Hessel-Pras
- German Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.
| |
Collapse
|
|
5
|
Avigan MI, Mozersky RP, Seeff LB. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States. Int J Mol Sci 2016; 17:331. [PMID: 26950122 PMCID: PMC4813193 DOI: 10.3390/ijms17030331] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 02/16/2016] [Accepted: 02/16/2016] [Indexed: 01/06/2023] Open
Abstract
In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.
Collapse
Affiliation(s)
- Mark I Avigan
- Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
| | - Robert P Mozersky
- Office of Dietary Supplement Products, Center for Food Safety and Applied Nutrition, 5100 Paint Branch Parkway, College Park, MD 20740, USA.
| | | |
Collapse
|
|
6
|
Teschke R, Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps. Front Pharmacol 2015; 6:72. [PMID: 25954198 PMCID: PMC4407580 DOI: 10.3389/fphar.2015.00072] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 03/18/2015] [Indexed: 12/19/2022] Open
Abstract
Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.
Collapse
Affiliation(s)
- Rolf Teschke
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt MainFrankfurt, Germany
| | | |
Collapse
|
|
7
|
Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a tabular compilation of reported cases. Liver Int 2012; 32:1543-56. [PMID: 22928722 DOI: 10.1111/j.1478-3231.2012.02864.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 07/23/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. AIMS To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. METHODS A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. RESULTS A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). CONCLUSIONS This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future.
Collapse
Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University, Frankfurt/Main, Germany.
| | | | | | | | | |
Collapse
|
|
8
|
Wiedenfeld H. Plants containing pyrrolizidine alkaloids: toxicity and problems. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2011; 28:282-92. [PMID: 21360374 DOI: 10.1080/19440049.2010.541288] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Pyrrolizidine alkaloids (PA) are toxic for human and livestock. They undergo a metabolic toxication process in the liver which is the first target organ for PA poisoning. Worldwide many episodes of human PA intoxications are well reported. In many cases the reason for these intoxications has been PA contamination in food. The main tools for analysing food and fodder on PA content are based on GC and HPLC separation, followed by MS(-MS) detection. Actual incidents with toxic PA are the 'Jacobaea vulgaris (syn. Senecio jacobaea) problem' in Europe and the 'Ageratum conyzoides problem' in Ethiopia.
Collapse
Affiliation(s)
- H Wiedenfeld
- Pharmaceutical Institute, University of Bonn, Bonn, Germany.
| |
Collapse
|
|
9
|
Abstract
There is appropriate concern about the potential risk for hepatotoxicity from herbal products because they are unregulated and therefore not standardized with regard to their contents. This is particularly the case for the crude herbals that are commonly formulated as a mixture, so that their ingredients may be ambiguous and even contain harmful contaminants. Presented here is an overview of the more commonly recognized herbal products that have been reported to be associated with liver injury. Although many of them are clearly implicated, there are some, particularly those identified solely through an occasional case report, for which the relationship is uncertain.
Collapse
Affiliation(s)
- Leonard B Seeff
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 31 Center Drive, Room 9A27, Bethesda, MD 20892, USA.
| |
Collapse
|
|
10
|
Stickel F, Schuppan D. Herbal medicine in the treatment of liver diseases. Dig Liver Dis 2007; 39:293-304. [PMID: 17331820 DOI: 10.1016/j.dld.2006.11.004] [Citation(s) in RCA: 216] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Revised: 10/02/2006] [Accepted: 11/06/2006] [Indexed: 12/11/2022]
Abstract
Herbal drugs have become increasingly popular and their use is widespread. Licensing regulations and pharmacovigilance regarding herbal products are still incomplete and clearcut proof of their efficacy in liver diseases is sparse. Nevertheless, a number of herbals show promising activity including silymarin for antifibrotic treatment, phyllantus amarus in chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis, and a number of herbal combinations from China and Japan that deserve testing in appropriate studies. Apart from therapeutic properties, reports are accumulating about liver injury after the intake of herbals, including those advertised for liver diseases. Acute and/or chronic liver damage occurred after ingestion of some Chinese herbs, herbals that contain pyrrolizidine alkaloids, germander, greater celandine, kava, atractylis gummifera, callilepsis laureola, senna alkaloids, chaparral and many others. Since the evidence supporting the use of botanicals to treat chronic liver diseases is insufficient and only few of them are well standardised and free of potential serious side effects, most of these medications are not recommended outside clinical trials. Particularly with regard to the latter, adequately powered randomised-controlled clinical trials with well-selected end points are needed to assess the role of herbal therapy for liver diseases.
Collapse
Affiliation(s)
- F Stickel
- Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland.
| | | |
Collapse
|
|
11
|
Affiliation(s)
- Felix Stickel
- Department of Medicine, Salem Medical Center, Heidelberg, Germany
| | | | | |
Collapse
|
|
12
|
Elvin-Lewis M. Safety issues associated with herbal ingredients. ADVANCES IN FOOD AND NUTRITION RESEARCH 2005; 50:219-313. [PMID: 16263432 DOI: 10.1016/s1043-4526(05)50007-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Affiliation(s)
- Memory Elvin-Lewis
- Department of Biology, Washington University, St. Louis, Missouri 63130, USA
| |
Collapse
|
|
13
|
Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms. Drug Metab Rev 2004; 36:1-55. [PMID: 15072438 DOI: 10.1081/dmr-120028426] [Citation(s) in RCA: 377] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Pyrrolizidine alkaloid-containing plants are widely distributed in the world and are probably the most common poisonous plants affecting livestock, wildlife, and humans. Because of their abundance and potent toxicities, the mechanisms by which pyrrolizidine alkaloids induce genotoxicities, particularly carcinogenicity, were extensively studied for several decades but not exclusively elucidated until recently. To date, the pyrrolizidine alkaloid-induced genotoxicities were revealed to be elicited by the hepatic metabolism of these naturally occurring toxins. In this review, we present updated information on the metabolism, metabolizing enzymes, and the mechanisms by which pyrrolizidine alkaloids exert genotoxicity and tumorigenicity.
Collapse
Affiliation(s)
- Peter P Fu
- National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
| | | | | | | |
Collapse
|
|
14
|
Affiliation(s)
- Mario Chojkier
- Department of Medicine and Center for Molecular Genetics, Veterans Affairs Healthcare System and University of California San Diego, VAMC (111-D), San Diego, CA 92161, USA.
| |
Collapse
|
|
15
|
Abstract
The early prognostic indicators for acute liver failure in endemic zones for hepatitis E virus have not been determined. All consecutive patients with acute liver failure from a geographically defined region endemic for hepatitis E virus were studied over the period April 1989-April 1996. Demographic, clinical and biochemical parameters were recorded at presentation and serum samples were analysed for known viral hepatitis (A-E) markers. Multiple parameters were compared in survivors and non-survivors in a univariate analysis. All significant factors on univariate analysis were entered into a stepwise logistic regression analysis to identify independent variables of prognosis. The sensitivity and specificity of significant prognostic factors was then assessed. A total of 180 [69 males and 111 females: age (mean +/- SD) 31.1 +/- 14.7 years] with acute liver failure were studied. Of these, 131 (72.8%) patients died. Hepatitis E virus was the aetiological cause in 79 (43.9%) patients, while hepatitis A virus, hepatitis B virus, hepatitis C virus and non-A, non-E agent/'s could be incriminated in four (2.1%), 25 (13.9%), 13 (7.2%) and 56 (31.1%) patients respectively. Of 83 women in childbearing age, 49 (59.0%) were pregnant, 33 (67.3%) of these were in the third trimester. Forty-seven (95.8%) pregnant women had HEV infection. Nine variables differed significantly between survivors and non-survivors on univariate analysis. Of these, four variables which predicted the adverse outcome on multivariate analysis were non-hepatitis-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years in that order of significance. Pregnancy per se or duration of gestation did not adversely affect the prognosis. In endemic areas, hepatitis E virus is the commonest cause of acute liver failure. Acute liver failure occurs in a high proportion of pregnant women, mostly in third trimester. Early predictors of a poor outcome are non-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years.
Collapse
Affiliation(s)
- M S Khuroo
- Department of Gastroenterology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar Kashmir, India.
| | | |
Collapse
|
|
16
|
Kumar S, DeLeve LD, Kamath PS, Tefferi A. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 2003; 78:589-98. [PMID: 12744547 DOI: 10.4065/78.5.589] [Citation(s) in RCA: 123] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatic veno-occlusive disease (VOD), increasingly referred to as sinusoidal obstruction syndrome, is a well-recognized complication of hematopoietic stem cell transplantation and contributes to considerable morbidity and mortality. In the Western Hemisphere, VOD, classified as a conditioning-related toxicity, is most commonly caused by stem cell transplantation. VOD has been described after all types of stem cell transplantation, irrespective of the stem cell source, type of conditioning therapy, or underlying disease. Recognition of this disease in the posttransplantation setting remains a challenge in the absence of specific diagnostic features because many other more common conditions can mimic it. Limited therapeutic or preventive strategies are currently available for the management of VOD. In this review, we provide a comprehensive account of the pathophysiology of this disease as we understand it today, risk factors for its development, and the current state of knowledge regarding preventive and therapeutic options.
Collapse
Affiliation(s)
- Shaji Kumar
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA
| | | | | | | |
Collapse
|
|
17
|
Affiliation(s)
- Roger A Coulombe
- Department of Veterinary Sciences, Utah State University, Logan, UT 84322-4620, USA
| |
Collapse
|
|
18
|
Abstract
Pyrrolizidine poisoning in humans is regarded by most clinical toxicologists as of little relevance. However, a number of individual case studies in the West and some severe cases of mass poisoning by contaminated grains have led to increased interest in these alkaloids. The increasing use of herbal remedies, some of which contain toxic pyrrolizidines, suggests that the incidence of pyrrolizidine poisoning is likely to increase. In this review the authors describe the chemistry and metabolism of pyrrolizidine alkaloids, the salient features of pyrrolizidine poisoning, and the methods available for detection of these compounds in human fluids.
Collapse
Affiliation(s)
- M J Stewart
- Indigenous Toxicology Unit, Department of Chemical Pathology, South African Institute for Medical Research, University of the Witwatersrand Medical School, Johannesburg, South Africa.
| | | |
Collapse
|
|
19
|
Abstract
During the latter part of this century the practice of herbalism has become mainstream throughout the world. This is due in part to the recognition of the value of traditional medical systems, particularly of Asian origin, and the identification of medicinal plants from indigenous pharmacopeias that have been shown to have significant healing power, either in their natural state or as the source of new pharmaceuticals. Generally these formulations are considered moderate in efficacy and thus less toxic than most pharmaceutical agents. In the Western world, in particular, the developing concept that 'natural' is better than 'chemical' or 'synthetic' has led to the evolution of Neo-Western herbalism that is the basis of an ever expanding industry. In the US, often guised as food, or food supplements, known as nutriceuticals, these formulations are readily available for those that wish to self-medicate. Within this system, in particular, are plants that lack ethnomedical verification of efficacy or safety. Unfortunately there is no universal regulatory system in place that insures that any of these plant remedies are what they say they are, do what is claimed, or most importantly are safe. Data will be presented in this context, outlining how adulteration, inappropriate formulation, or lack of understanding of plant and drug interactions have led to adverse reactions that are sometimes life-threatening or lethal.
Collapse
Affiliation(s)
- M Elvin-Lewis
- Department of Biology, Washington University, Box 1137, St. Louis, MO 63130-4899, USA.
| |
Collapse
|
|
20
|
Abstract
OBJECTIVE Hepatic impairment resulting from the use of conventional drugs is widely acknowledged, but there is less awareness of the potential hepatotoxicity of herbal preparations and other botanicals, many of which are believed to be harmless and are commonly used for self-medication without supervision. The aim of this paper is to examine the evidence for hepatotoxicity of botanicals and draw conclusions regarding their pathology, safety and applications. DESIGN Current literature on the hepatotoxicity of herbal drugs and other botanicals is reviewed. The aetiology, clinical picture and treatment of mushroom (Amanita) poisoning are described. RESULTS Hepatotoxic effects have been reported for some Chinese herbal medicines (such as Jin Bu Huan, Ma-Huang and Sho-saiko-to), pyrrolizidine alkaloid-containing plants, germander (Teucrium chamaedrys), chaparral (Larrea tridentata), Atractylis gummifera, Callilepsis laureola, and others. The frequency with which botanicals cause hepatic damage is unclear. There is a lack of controlled treatment trials and the few studies published to date do not clarify the incidence of adverse effects. Many plant products do not seem to lead to toxic effects in everyone taking them, and they commonly lack a strict dose-dependency. For some products, such as Sho-saiko-to, the picture is confused further by demonstrations of hepatoprotective properties for some components. Mushroom poisoning is mostly due to the accidental consumption of Amanita species. Treatment with silymarin, thioctic acid, penicillin and liver transplantation have been shown to be effective but require early diagnosis. CONCLUSIONS Severe liver injury, including acute and chronic abnormalities and even cirrhotic transformation and liver failure, has been described after the ingestion of a wide range of herbal products and other botanical ingredients, such as mushrooms. It is concluded that in certain situations herbal products may be just as harmful as conventional drugs.
Collapse
Affiliation(s)
- F Stickel
- Department of Medicine and Gastroenterology, Krankenhaus der Barmherzigen Brüder, Technical University of Munich, D-80639, Munich, Germany
| | | | | |
Collapse
|
|
21
|
|
|
22
|
Marsa-Vila L, Gorin NC, Laporte JP, Labopin M, Dupuy-Montbrun MC, Fouillard L, Isnard F, Najman A. Prophylactic heparin does not prevent liver veno-occlusive disease following autologous bone marrow transplantation. Eur J Haematol 1991; 47:346-54. [PMID: 1761121 DOI: 10.1111/j.1600-0609.1991.tb01859.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Veno-occlusive disease (VOD) is a major cause of toxic death after autologous bone marrow transplantation (ABMT). We studied the potential role of continuous administration of low-dose heparin for VOD prevention in 234 consecutive patients who underwent ABMT in our institution. The population consisted of 98 patients autografted before October 1984 who did not receive heparin, and a series of 136 patients autografted from October 1984 to March 1989 containing 98 patients included in a randomized trial comparing heparin administration (n = 52) vs no heparin (n = 46), and an additional group of 38 patients who received non-randomized heparin in view of high-risk criteria to develop VOD (n = 31) or other reasons unrelated to VOD (n = 7). Overall, 90 patients (38%) received heparin and 144 (62%) did not. The global incidence of VOD was 13/234 (5-5%). Heparin did not reduce the risk of VOD in all subgroups studied. In particular, in the randomized trial, the incidence of VOD was 2.2% in the group without heparin vs 7-7% in the group receiving heparin. We analyzed in depth the 13 patients who developed VOD and we compared them to a control group of 13 patients pair-matched for age, sex, diagnosis and preparative regimen, who did not develop VOD. We found that abnormal LFT before ABMT predisposed patients to VOD; refractoriness to platelet transfusion was observed in 85% of the patients in the VOD group vs 15% in the control group (p less than 0.05). VOD patients had an increased requirement for red cells and platelet transfusions, a lower recovery (R less than 25%) after the second and third platelet transfusion, and shorter intervals separating the first four platelet transfusions. Further, the platelet reconstitution after ABMT in the VOD group was slower in comparison to the control group (p less than 0.01). Again, in this pair-matched analysis continuous infusion of low-dose heparin did not prevent VOD.
Collapse
Affiliation(s)
- L Marsa-Vila
- Hopital Saint Antoine, Department of Hematology, Paris, France
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Nyarko AA, Addy ME. Effect of aqueous extract ofAdenia cissampeloides on blood pressure and serum analytes of hypertensive patients. Phytother Res 1990. [DOI: 10.1002/ptr.2650040107] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|
|
24
|
Abstract
Herbs, herbal products, food additives and other dietary supplements derived from plants are widely consumed in many countries. The literature on intoxications from such behaviour is increasing. This article reviews some of the factors predisposing to intoxication from the use of herbs, with examples drawn largely from pyrrolizidine alkaloid-containing plants. Poisonings occur because of the misidentification of a plant, or the unknown or ignored toxicity of a correctly identified plant. Factors contributing to problems include the difficulties of identifying chopped, processed herbs or plant mixtures, persistent use of a toxic plant, variability in the toxic constituents of a plant, problems of nomenclature, adulteration and the difficulty in establishing the chronic toxic potential of a plant. Certain users of herbs are at high risk of intoxication. These include chronic users, those consuming large amounts or a great variety, the very young, fetuses, the elderly, the sick, the malnourished or undernourished and those on long term medication. Members of certain cultural groups in North America are also at higher risk. Certain plant toxins may be gender-selective in their action. To encourage discussion, some approaches to regulation are suggested, and some commonsense guidelines are given.
Collapse
Affiliation(s)
- R J Huxtable
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson
| |
Collapse
|
|
25
|
Affiliation(s)
- P M Ridker
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | | |
Collapse
|
|
26
|
Abstract
Portal hypertension occurs in several aetiologically distinct disease states associated with either increased flow or increased resistance in the portal venous system. The morbidity and mortality observed are the result of ascites formation, impaired hepatic metabolism, encephalopathy and, most ominously, variceal haemorrhage. Patients with conditions in which there is relatively little hepatic parenchymal damage (non-cirrhotic portal hypertension) tend to have fewer episodes of encephalopathy and are better able to tolerate bleeding episodes than those patients with underlying cirrhosis. Similarly, the development of ascites varies with respect to the aetiology of the portal hypertension. This chapter discusses the natural history of the various disease states that manifest portal hypertension, thus allowing critical evaluation of the various therapeutic modalities used in its treatment.
Collapse
Affiliation(s)
- J B Ready
- University of Colorado Health Sciences Center, Denver
| | | |
Collapse
|
|
27
|
Addy ME, Nyarko AK. Diabetic patients' response to oral administration of aqueous extract ofIndigofera arrecta. Phytother Res 1988. [DOI: 10.1002/ptr.2650020409] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
|
|
28
|
Kumana CR, Ng M, Lin HJ, Ko W, Wu PC, Todd D. Herbal tea induced hepatic veno-occlusive disease: quantification of toxic alkaloid exposure in adults. Gut 1985; 26:101-4. [PMID: 3965360 PMCID: PMC1432401 DOI: 10.1136/gut.26.1.101] [Citation(s) in RCA: 69] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Four young Chinese women took daily doses of an unidentified 'Indian' herbal tea as treatment for psoriasis. Three (one of whom died), developed ascites, hepatomegaly and biochemical abnormalities within 19-45 days. The fourth patient discontinued herbal tea after 21 days when she developed a skin rash. Two patients had portal hypertension, while all had liver histology showing features of veno-occlusive disease. Pyrrolizidine alkaloids were identified spectrophotometrically in the brewed tea, and in the chopped leaves of the herbal mixture; the mean dose in the tea prepared for consumption being 12 mg/day of alkaloid base and 18 mg/day of N-oxide. The mean cumulative dose of alkaloids (base + N-oxide) before onset of symptoms (three patients), was estimated to be 18 mg/kg. In the asymptomatic patient with histological liver disease only, the corresponding dose was 15 mg/kg. These cases thus provide some measure of pyrrolizidine alkaloid toxicity in adults.
Collapse
|
|
29
|
|
|
30
|
|
|
31
|
Culvenor CC. Estimated intakes of pyrrolizidine alkaloids by humans. A comparison with dose rates causing tumors in rats. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1983; 11:625-35. [PMID: 6620404 DOI: 10.1080/15287398309530372] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Pyrrolizidine alkaloid poisoning in humans is associated with the consumption of plants containing the alkaloids, either as contaminants of grains or as infusions for medicinal purposes. The alkaloids are carcinogenic in rats but have not been associated, so far, with tumors in humans. For the known instances of human intake of pyrrolizidine alkaloids, the main alkaloids involved and estimated consumption rates have been tabulated. These rates are compared with the dose rates of the same or similar alkaloids that lead to a significant tumor incidence in experimental rats. In the more chronic poisoning outbreaks, the intake rate is comparable with a carcinogenic dose in rats. The long-term observation of survivors of these outbreaks would offer an opportunity for determining whether pyrrolizidine alkaloids are carcinogenic in humans.
Collapse
|
|
32
|
Khuroo MS, Datta DV. Budd-Chiari syndrome following pregnancy. Report of 16 cases, with roentgenologic, hemodynamic and histologic studies of the hepatic outflow tract. Am J Med 1980; 68:113-121. [PMID: 7350798 DOI: 10.1016/0002-9343(80)90180-1] [Citation(s) in RCA: 113] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Budd-Chiari syndrome following pregnancy is an extremely rare disease as reported in the literature. Reported here are 16 such cases in a total of 105 patients with Budd-Chiari syndrome seen at Postgraduate Institute of Medical Education and Research, Chandigarh, from 1963 to 1978. The clinical pointer to the diagnosis was sudden occurrence of abdominal pain and ascites following childbirth. Eleven patients had diuretic-resistant ascites. Percutaneous hepatography was valuable in detecting the site and the nature of the outflow block. The prognosis was uniformly bad, and eight patients died within one year from the onset of their illness. The various treatment schedules, including anticoagulant therapy, Rhodiascit ascitic fluid re-infusion and portasystemic shunt surgery, had no beneficial effect on the survival of these patients.
Collapse
|