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Frontiers of Medicine

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Front. Med.    2015, Vol. 9 Issue (4) : 457-467    https://doi.org/10.1007/s11684-015-0417-8
RESEARCH ARTICLE
Evidence chain-based causality identification in herb-induced liver injury: exemplification of a well-known liver-restorative herb Polygonum multiflorum
Jiabo Wang1,Zhijie Ma1,2,Ming Niu1,Yun Zhu1,5,Qingsheng Liang3,Yanling Zhao1,Jingyuan Song4,Zhaofang Bai1,Yaming Zhang1,Ping Zhang5,Na Li1,Yakun Meng1,Qi Li1,Lushan Qin1,Guangju Teng3,Junling Cao6,Baosen Li3,Shilin Chen4,Yonggang Li7,*(),Zhengsheng Zou3,*(),Honghao Zhou8,*(),Xiaohe Xiao5,*()
1. China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China
2. Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
3. Diagnosis and Treatment Center for Non-infectious Diseases, 302 Military Hospital, Beijing 100039, China
4. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
5. Integrative Medical Center, 302 Military Hospital, Beijing 100039, China
6. Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
7. Diagnosis and Treatment Center of Western and Chinese Medicine for Liver Diseases, 302 Military Hospital, Beijing 100039, China
8. Institute of Clinical Pharmacology, Central South University, Changsha 410008, China
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Abstract

Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury (DILI) in the United States. However, reliable methods to identify the DILI causality of some herbs, such as Heshouwu (dried root of Polygonum multiflorum), remain lacking. In this study, a total of 12 307 inpatients with liver dysfunction and 147 literature-reported cases of Heshouwu DILI were screened. A general algorithm indicated that only 22.5% (9/40) and 30.6% (45/147) of all hospitalization and literature case reports, respectively, demonstrate the high probability of DILI causality of Heshouwu. By contrast, 95% (19/20) of all cases prospectively investigated by pharmacognosy, phytochemistry, and metabolomic tests exhibited highly probable causality, including a patient who was previously incorrectly attributed and a case that was excluded from Heshouwu causality by pharmacognostic evidence. Toxin (heavy metals, pesticides, and mycotoxins) contamination was also excluded from Heshouwu DILI causality. The objectivity of these screening methods for Heshouwu DILI diagnosis addresses safety concerns regarding stilbene-containing herbal medicines and dietary supplements.
Keywords drug-induced liver injury      pharmacognosy      metabolomics      stilbene      Polygonum multiflorum      Chinese herbal medicine     
Corresponding Author(s): Yonggang Li,Zhengsheng Zou,Honghao Zhou,Xiaohe Xiao   
Just Accepted Date: 09 September 2015   Online First Date: 09 October 2015    Issue Date: 26 November 2015
 Cite this article:   
Ming Niu,Jiabo Wang,Qingsheng Liang, et al. Evidence chain-based causality identification in herb-induced liver injury: exemplification of a well-known liver-restorative herb Polygonum multiflorum[J]. Front. Med., 2015, 9(4): 457-467.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0417-8
https://academic.hep.com.cn/fmd/EN/Y2015/V9/I4/457
Fig.1  Stepwise strategy for causality assessment of herbal DILI based on RUCAM.
Assessments Methods/items Score
RUCAM
1–7 Time of onset / Course / Risk factors / Concomitant drug(s) / Nondrug causes / Previous ?information / Rechallenge −9−10
ECCIA
8 Metabolomics
?Suggestive to DILI +3
?Not suggestive to DILI 0
?Suggestive to AIH −3
9 Pharmacognosy*
?Authentic 3
?Not applicable 0
?Fraudulent or contaminated with toxins −3
10 In vivo phytochemistry
?Presence of characteristic metabolites +3
?None presence 0
Tab.1  Evidence Chain-based Causality Identification Algorithm (ECCIA) for herbal medicine-induced liver injury on the bases of RUCAM
Fig.2  Liver biopsy, metabolomic, and in vivo chemical identification analyses of Heshouwu-induced liver injury in patients. (A) Representative liver biopsy of a Heshouwu DILI patient with hepatocellular necrosis, lobular portal inflammation, and enlargement and congestion in the sinusoid. (B) PCA- and PLS-DA-based metabolomic differentiation of Heshouwu DILI from AIH and HBV. The Heshouwu DILI cases were separated clearly from AIH and clustered with other DILI cases induced by other known drugs. Blue triangles represent “DILI,” red circles represent “AIH,” and black boxes represent “HBV.” (C) Background mass spectra of sera. (D) Chromatogram and mass spectra of emodin glucuronide in Heshouwu in patients’ sera. (E) Chromatogram and mass spectra of TSG glucuronide in Heshouwu in patients’ sera.
Fig.3  Pharmacognostic authentication of the digested materials of patients. (A) Photographs of ancient record and the plant and sliced root of P. multiflorum. The left photograph describes the “male” and “female” forms of Heshouwu in the Compendium of Materia Medica, which was written by Shi-zhen Li in the Ming Dynasty of China. The top right photographs present the plant and sliced root of P. multiflorum used as authenticated Heshouwu in China. The lower right photograph shows the plant and sculptured root of Musa basjioo Sied. et Zucc., which is misused as fraudulent Heshouwu. (B) DNA barcoding authentication shows the P. multiflorum species in the patient’s digested material. (C) Representative microscopic photographs of the patient’s digested material show the characteristic features of heat-prepared P. multiflorum, e.g., fiber cells, brown cells, and vessel cells. (D) HPLC fingerprints show similar characteristic peaks between the patients’ digested materials and authenticated P. multiflorum. Characteristic peaks were identified by the reference substances and mass spectrometry. (E) Mass spectra of the characteristic peaks.
Fig.4  Complete identification and exclusion flow of suspected Heshouwu DILI by ECCIA. N.A., not applicable; A, authentic; F, fraudulent.
1 Chalasani  NP, Hayashi  PH, Bonkovsky  HL, Navarro  VJ, Lee  WM, Fontana  RJ; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014; 109(7): 950–966, quiz 967
https://doi.org/10.1038/ajg.2014.131 pmid: 24935270
2 Danan  G, Benichou  C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46(11): 1323–1330
https://doi.org/10.1016/0895-4356(93)90101-6 pmid: 8229110
3 Maria  VAJ, Victorino  RMM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26(3): 664–669
https://doi.org/10.1002/hep.510260319 pmid: 9303497
4 Rockey  DC, Seeff  LB, Rochon  J, Freston  J, Chalasani  N, Bonacini  M, Fontana  RJ, Hayashi  PH; US Drug-Induced Liver Injury Network. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method. Hepatology 2010; 51(6): 2117–2126
https://doi.org/10.1002/hep.23577 pmid: 20512999
5 Rochon  J, Protiva  P, Seeff  LB, Fontana  RJ, Liangpunsakul  S, Watkins  PB, Davern  T, McHutchison  JG; Drug-Induced Liver Injury Network (DILIN). Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury. Hepatology 2008; 48(4): 1175–1183
https://doi.org/10.1002/hep.22442 pmid: 18798340
6 Barritt  AS, Lee  J, Hayashi  PH. Detective work in drug-induced liver injury: sometimes it is all about interviewing the right witness. Clin Gastroenterol Hepato, 2010, 8(7): 635–637
7 De Smet  PA. Herbal medicine in Europe—relaxing regulatory standards. N Engl J Med 2005; 352(12): 1176–1178
https://doi.org/10.1056/NEJMp048083 pmid: 15788494
8 Teschke  R, Eickhoff  A, Wolff  A, Frenzel  C, Schulze  J. Herbal hepatotoxicity and WHO global introspection method. Ann Hepatol 2013; 12(1): 11–21
pmid: 23293189
9 Teschke  R, Bahre  R, Genthner  A, Fuchs  J, Schmidt-Taenzer  W, Wolff  A. Suspected black cohosh hepatotoxicity—challenges and pitfalls of causality assessment. Maturitas 2009; 63(4): 302–314
https://doi.org/10.1016/j.maturitas.2009.05.006 pmid: 19586731
10 Teschke  R. Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review. Menopause 2010; 17(2): 426–440
https://doi.org/10.1097/gme.0b013e3181c5159c pmid: 20216279
11 Teschke  R, Frenzel  C, Schulze  J, Eickhoff  A. Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: was causality adequately ascertained? Regul Toxicol Pharmacol 2012; 63(1): 1–9
https://doi.org/10.1016/j.yrtph.2012.02.009 pmid: 22381150
12 Teschke  R, Schmidt-Taenzer  W, Wolff  A. USP suspected herbal hepatotoxicity: quality of causality assessment is more important than quantity of counted cases, not vice versa. Pharmocoepidemiol Drug Saf 2012; 21(3): 336–338
https://doi.org/10.1002/pds.3209
13 Howitz  KT, Bitterman  KJ, Cohen  HY, Lamming  DW, Lavu  S, Wood  JG, Zipkin  RE, Chung  P, Kisielewski  A, Zhang  LL, Scherer  B, Sinclair  DA. Small molecule activators of sirtuins extend Saccharomy<?A3B2 tpb=-0.5pt?>ces cerevisiae lifespan. Nature 2003; 425(6954): 191–196
https://doi.org/10.1038/nature01960 pmid: 12939617
14 Hubbard  BP, Gomes  AP, Dai  H, Li  J, Case  AW, Considine  T, Riera  TV, Lee  JE, e  SY, Lamming  DW, Pentelute  BL, Schuman  ER, Stevens  LA, Ling  AJ, Armour  SM, Michan  S, Zhao  H, Jiang  Y, Sweitzer  SM, Blum  CA, Disch  JS, Ng  PY, Howitz  KT, Rolo  AP, Hamuro  Y, Moss  J, Perni  RB, Ellis  JL, Vlasuk  GP, Sinclair  DA. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 2013; 339(6124): 1216–1219
https://doi.org/10.1126/science.1231097 pmid: 23471411
15 Morselli  E, Maiuri  MC, Markaki  M, Megalou  E, Pasparaki  A, Palikaras  K, Criollo  A, Galluzzi  L, Malik  SA, Vitale  I, Michaud  M, Madeo  F, Tavernarakis  N, Kroemer  G. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis 2010; 1(1): e10
https://doi.org/10.1038/cddis.2009.8 pmid: 21364612
16 Wang  JB, Xiao  XH, Du  XX, Zou  ZS, Song  HB, Guo  XX. Identification and early diagnosis for traditional Chinese medicine-induced liver injury based on translational toxicology. Zhongguo Zhong Yao Za Zhi 2014; 39(1): 5–9 (in Chinese)
pmid: 24754159
17 Wang  J, Zou  Z, Zhao  Y, Qin  L, Li  Q, Ma  Z, Du  X, Xiao  X. Metabonomic biomarkers for drug-induced liver injury in rats and humans: better than alanine aminotransferase? Hepatology 2013; 58(4): A379–A380
18 Boocock  DJ, Faust  GE, Patel  KR, Schinas  AM, Brown  VA, Ducharme  MP, Booth  TD, Crowell  JA, Perloff  M, Gescher  AJ, Steward  WP, Brenner  DE. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 2007; 16(6): 1246–1252
https://doi.org/10.1158/1055-9965.EPI-07-0022 pmid: 17548692
19 Xiaojing  W, Liang  Z, Chen  HB, Zhao  Z, Li  P. Identification of Daqingye and Banlangen including crude drugs and decoction dregs from three plant species by normal light and fluorescence microscopy. Microsc Res Tech 2013; 76(8): 774–782
https://doi.org/10.1002/jemt.22228 pmid: 23681767
20 Chen  S, Xu  J, Liu  C, Zhu  Y, Nelson  DR, Zhou  S, Li  C, Wang  L, Guo  X, Sun  Y, Luo  H, Li  Y, Song  J, Henrissat  B, Levasseur  A, Qian  J, Li  J, Luo  X, Shi  L, He  L, Xiang  L, Xu  X, Niu  Y, Li  Q, Han  MV, Yan  H, Zhang  J, Chen  H, Lv  A, Wang  Z, Liu  M, Schwartz  DC, Sun  C. Genome sequence of the model medicinal mushroom Ganoderma lucidum. Nat Commun 2012; 3: 913
https://doi.org/10.1038/ncomms1923 pmid: 22735441
21 Qiu  X, Zhang  J, Huang  Z, Zhu  D, Xu  W. Profiling of phenolic constituents in Polygonum multiflorum Thunb. by combination of ultra-high-pressure liquid chromatography with linear ion trap-Orbitrap mass spectrometry. J Chromatogr A 2013; 1292: 121–131
https://doi.org/10.1016/j.chroma.2012.11.051 pmid: 23246090
22 The State Pharmacopoeia Commission of PR China. First Div., Appendix XID. Pharmacopoeia of the People’s Republic of China. Beijing: Chemical Industry Press, 2010: Appendix 67
23 Chen  X, Bian  Z, Hou  H, Yang  F, Liu  S, Tang  G, Hu  Q. Development and validation of a method for the determination of 159 pesticide residues in tobacco by gas chromatography-tandem mass spectrometry. J Agric Food Chem 2013; 61(24): 5746–5757
https://doi.org/10.1021/jf400887x pmid: 23701289
24 Dalton  HR, Fellows  HJ, Stableforth  W, Joseph  M, Thurairajah  PH, Warshow  U, Hazeldine  S, Remnarace  R, Ijaz  S, Hussaini  SH, Bendall  RP. The role of hepatitis E virus testing in drug-induced liver injury. Aliment Pharmacol Ther 2007; 26(10): 1429–1435
https://doi.org/10.1111/j.1365-2036.2007.03504.x pmid: 17850420
25 Davern  TJ, Chalasani  N, Fontana  RJ, Hayashi  PH, Protiva  P, Kleiner  DE. Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology, 2011, 141: 1665–1672 e1–9
26 Zachou  K, Muratori  P, Koukoulis  GK, Granito  A, Gatselis  N,  Fabbri  A, Dalekos  GN, Muratori  L. Review article: autoimmune hepatitis — current management and challenges. Aliment Pharmacol Ther 2013; 38(8): 887–913
https://doi.org/10.1111/apt.12470 pmid: 24010812
27 Wang  JB, Pu  SB, Sun  Y, Li  ZF, Niu  M, Yan  XZ, Zhao  YL, Wang  LF, Qin  XM, Ma  ZJ, Zhang, YM, Li  BS, Luo  SQ, Gong  M, Sun  YQ, Zou  ZS, Xiao  XH. Metabolomic profiling of autoimmune hepatitis: the diagnostic utility of nuclear magnetic resonance spectroscopy. J Proteome Res 2014; 13(8): 3792–3801
28 Coghlan  ML, Haile  J, Houston  J, Murray  DC, White  NE, Moolhuijzen  P, Bellgard  MI, Bunce  M. Deep sequencing of plant and animal DNA contained within traditional Chinese medicines reveals legality issues and health safety concerns. PLoS Genet 2012; 8(4): e1002657
https://doi.org/10.1371/journal.pgen.1002657 pmid: 22511890
29 Gökmen  MR, Cosyns  JP, Arlt  VM, Stiborová  M, Phillips  DH, Schmeiser  HH, Simmonds  MS, Cook  HT, Vanherweghem  JL, Nortier  JL, Lord  GM. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med 2013; 158(6): 469–477
https://doi.org/10.7326/0003-4819-158-6-201303190-00006 pmid: 23552405
30 Ma  J, Zheng  L, Deng  T, Li  CL, He  YS, Li  HJ, Li  P. Stilbene glucoside inhibits the glucuronidation of emodin in rats through the down-regulation of UDP-glucuronosyltransferases 1A8: application to a drug-drug interaction study in Radix Polygoni Multiflori. J Ethnopharmacol 2013; 147(2): 335–340
https://doi.org/10.1016/j.jep.2013.03.013 pmid: 23523942
31 Wu  X, Chen  X, Huang  Q, Fang  D, Li  G, Zhang  G. Toxicity of raw and processed roots of Polygonum multiflorum. Fitoterapia 2012; 83(3): 469–475
https://doi.org/10.1016/j.fitote.2011.12.012 pmid: 22210538
32 Murias  M, Luczak  MW, Niepsuj  A, Krajka-Kuzniak  V, Zielinska-Przyjemska  M, Jagodzinski  PP, Jäger  W, Szekeres  T, Jodynis-Liebert  J. Cytotoxic activity of 3,3′,4,4′,5,5′-hexahydroxystilbene against breast cancer cells is mediated by induction of p53 and downregulation of mitochondrial superoxide dismutase. Toxicol In Vitro 2008; 22(5): 1361–1370
https://doi.org/10.1016/j.tiv.2008.03.002 pmid: 18434081
33 Ünsalan  O, Kuş  N, Jarmelo  S, Fausto  R. Trans- and cis-stilbene isolated in cryogenic argon and xenon matrices. Spectrochim Acta A Mol Biomol Spectrosc 2015: 136(A): 81–94
34 Lin  CM, Singh  SB, Chu  PS, Dempcy  RO, Schmidt  JM, Pettit  GR, Hamel  E. Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol 1988; 34(2): 200–208
pmid: 3412321
35 Siles  R, Ackley  JF, Hadimani  MB, Hall  JJ, Mugabe  BE, Guddneppanavar  R, Monk  KA, Chapuis  JC, Pettit  GR, Chaplin  DJ, Edvardsen  K, Trawick  ML, Garner  CM, Pinney  KG. Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents. J Nat Prod 2008; 71(3): 313–320
https://doi.org/10.1021/np070377j pmid: 18303849
36 Sun  J, Huang  X, Wu  H, Huang  F. HPLC/IT-MS analysis of glycosides in radix Polygoni multiflori. Nat Prod Res Dev 2009; 21: 806–812
37 Navarro  VJ, Lucena  MI. Hepatotoxicity induced by herbal and dietary supplements. Semin Liver Dis 2014; 34(2): 172–193
https://doi.org/10.1055/s-0034-1375958 pmid: 24879982
38 Verma  S, Thuluvath  PJ. Complementary and alternative medicine in hepatology: review of the evidence of efficacy. Clin Gastroenterol Hepatol 2007; 5(4): 408–416
https://doi.org/10.1016/j.cgh.2006.10.014 pmid: 17222587
39 Wu  X, Chen  X, Huang  Q, Fang  D, Li  G, Zhang  G. Toxicity of raw and processed roots of Polygonum multiflorum. Fitoterapia 2012; 83(3): 469–475
https://doi.org/10.1016/j.fitote.2011.12.012 pmid: 22210538
40 la Porte  C, Voduc  N, Zhang  G, Seguin  I, Tardiff  D, Singhal  N, Cameron  DW. Steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet 2010; 49(7): 449–454
https://doi.org/10.2165/11531820-000000000-00000 pmid: 20528005
41 Crowell  JA, Korytko  PJ, Morrissey  RL, Booth  TD, Levine  BS. Resveratrol-associated renal toxicity. Toxicol Sci 2004; 82(2): 614–619
https://doi.org/10.1093/toxsci/kfh263 pmid: 15329443
42 Popat  R, Plesner  T, Davies  F, Cook  G, Cook  M, Elliott  P, Jacobson  E, Gumbleton  T, Oakervee  H, Cavenagh  J. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol 2013; 160(5): 714–717
https://doi.org/10.1111/bjh.12154 pmid: 23205612
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