Herb-induced liver injury in the berlin case-control surveillance study

International Journal of Molecular Sciences

Volume 17, Issue 1, 15 January 2016, Article number 114

Open Access

  (Article)

Douros, A.^a , 

Bronder, E.^a , 

Andersohn, F.^b , 

Klimpel, A.^a , 

Kreutz, R.^a , 

Garbe, E.^ac , 

Bolbrinker, J.^a 

 

^a  Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
^b  Institute for Social Medicine, Epidemiology and Health Economy, Charité-Universitätsmedizin Berlin, Berlin, Germany
^c  Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology—BIPS, Bremen, Germany 

View additional affiliations

View references (39)

Abstract

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbalaetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Author keywords

Hepatotoxicity; Pharmacovigilance; Phytotherapeutics

Indexed keywords

EMTREE drug terms: alanine aminotransferase; antinuclear antibody; aspartate aminotransferase; bilirubin; corticosteroid; lead; metoprolol

EMTREE medical terms: abdominal pain; adult; Article; blood clotting disorder; cholestasis; clinical article; Eucalyptus globulus; fatigue; female;Germany; herb; herbal tea; human; hyperbilirubinemia; Hypericum perforatum; inflammation; jaundice; liver injury; liver necrosis; male; Mentha piperita; middle aged; Pelargonium; rash; Valeriana

Chemicals and CAS Registry Numbers: alanine aminotransferase, 9000-86-6, 9014-30-6; aspartate aminotransferase, 9000-97-9; bilirubin, 18422-02-1, 635-65-4; lead, 7439-92-1, 13966-28-4; metoprolol, 37350-58-6

ISSN: 16616596Source Type: Journal Original language: English

DOI: 10.3390/ijms17010114Document Type: Article

Publisher: MDPI AG

References (39)

View in search results format

• Page
 
• • Export |
  • Print |
  • E-mail |
  • Create bibliography

• 
  1

  Stickel, F., Shouval, D.

  Hepatotoxicity of herbal and dietary supplements: an update
  (2015) Archives of Toxicology, 89 (6), pp. 851-865. Cited 14 times.
  link.springer.de/link/service/journals/00204/index.htm
  doi: 10.1007/s00204-015-1471-3
  
• 
  2

  Navarro, V.J.

  Herbal and dietary supplement hepatotoxicity
  (2009) Seminars in Liver Disease, 29 (4), pp. 373-382. Cited 65 times.
  doi: 10.1055/s-0029-1240006
  
• 
  3

  Navarro, V.J., Barnhart, H., Bonkovsky, H.L., Davern, T., Fontana, R.J., Grant, L., Reddy, K.R., (...), Vuppalanchi, R.

  Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network
  (2014) Hepatology, 60 (4), pp. 1399-1408. Cited 34 times.
  http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350
  doi: 10.1002/hep.27317
  
• 
  4

  Teschke, R., Wolff, A., Frenzel, C., Schulze, J., Eickhoff, A.

  Herbal hepatotoxicity: A tabular compilation of reported cases
  (2012) Liver International, 32 (10), pp. 1543-1556. Cited 46 times.
  doi: 10.1111/j.1478-3231.2012.02864.x
  
• 
  5

  Calitz, C., Du Plessis, L., Gouws, C., Steyn, D., Steenekamp, J., Muller, C., Hamman, S.

  Herbal hepatotoxicity: Current status, examples, and challenges
  (2015) Expert Opinion on Drug Metabolism and Toxicology, 11 (10), pp. 1551-1565. Cited 4 times.
  doi: 10.1517/17425255.2015.1064110
  
• 
  6

  Geller, A.I., Shehab, N., Weidle, N.J., Lovegrove, M.C., Wolpert, B.J., Timbo, B.B., Mozersky, R.P., (...), Budnitz, D.S.

  Emergency department visits for adverse events related to dietary supplements
  (2015) New England Journal of Medicine, 373 (16), pp. 1531-1540. Cited 7 times.
  http://www.nejm.org/doi/pdf/10.1056/NEJMsa1504267
  doi: 10.1056/NEJMsa1504267
  
• 
  7

  Douros, A., Bronder, E., Andersohn, F., Klimpel, A., Thomae, M., Sarganas, G., Kreutz, R., (...), Garbe, E.

  Drug-induced liver injury: Results from the hospital-based Berlin Case-Control Surveillance Study
  (2015) British Journal of Clinical Pharmacology, 79 (6), pp. 988-999. Cited 5 times.
  http://www.bjcp-journal.com/
  doi: 10.1111/bcp.12565
  
• 
  8

  Wu, C.-H., Wang, C.-C., Kennedy, J.

  Changes in herb and dietary supplement use in the US adult population: A comparison of the 2002 and 2007 national health interview surveys
  (2011) Clinical Therapeutics, 33 (11), pp. 1749-1758. Cited 59 times.
  doi: 10.1016/j.clinthera.2011.09.024
  
• 
  9

  Dantuluri, S., North-Lewis, P., Karthik, S.V.

  Gotu Kola induced hepatotoxicity in a child-Need for caution with alternative remedies
  (2011) Digestive and Liver Disease, 43 (6), p. 500. Cited 5 times.
  doi: 10.1016/j.dld.2010.12.012
  
• 
  10

  Jorge, O.A., Jorge, A.D.

  Hepatotoxicity associated with the ingestion of Centella asiatica
  (2005) Revista Espanola de Enfermedades Digestivas, 97 (2), pp. 115-124. Cited 37 times.
  
• 
  11

  Teschke, R., Bahre, R.

  Severe hepatotoxicity by Indian ayurvedic herbal products: A structured causality assessment
  (2009) Annals of Hepatology, 8 (3), pp. 258-266. Cited 32 times.
  http://www.annalsofhepatology.com/PDF/HP93-15a-Severe15.pdf
  
• 
  12

  AkdÄ Hepatitis im Zusammenhang mit Umckaloabo®.
  (accessed on 7 October 2015)
  http://www.akdae.de/Arzneimittelsicherheit/Bekanntgaben/Archiv/2011/20110729.html
  

  •  
• 
  13

  Teschke, R., Frenzel, C., Schulze, J., Eickhoff, A.

  Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: Was causality adequately ascertained?
  (2012) Regulatory Toxicology and Pharmacology, 63 (1), pp. 1-9. Cited 30 times.
  doi: 10.1016/j.yrtph.2012.02.009
  
• 
  14

  Community herbal monograph on Pelargonium sidoides DC and/or Pelargonium reniforme Curt., radix.
  (accessed on 7 October 2015)
  http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_monograph/2013/02/WC500138439.pdf
  

  •  
• 
  15

  BfArM. Abwehr von Gefahren durch Arzneimittel, Stufe II: Pelargonium-Wurzel-Haltige Arzneimittel.
  (accessed on 17 October 2015)
  http://www.abda.de/fileadmin/assets/Arzneimittelkommission/PDF/Sonstiges_Anhaenge_fuer_Nachrichten/14_14_Info_Bescheid_Pelagoniumhaltige_Arzneimittel_BfArM.pdf
  

  •  
• 
  16

  Timmer, A., Günther, J., Motschall, E., Rücker, G., Antes, G., Kern, W.V.

  Pelargonium sidoides extract for treating acute respiratory tract infections.
  (2013) The Cochrane database of systematic reviews, 10, p. CD006323. Cited 8 times.
  
• 
  17

  Cohen, D.L., Toro, Y.D.

  A case of valerian-associated hepatotoxicity
  (2008) Journal of Clinical Gastroenterology, 42 (8), pp. 961-962. Cited 14 times.
  doi: 10.1097/MCG.0b013e3180500348
  
• 
  18

  MacGregor, F.B., Abernethy, V.E., Dahabra, S., Cobden, I., Hayes, P.C.

  Hepatotoxicity of herbal remedies
  (1989) British Medical Journal, 299 (6708), pp. 1156-1157. Cited 143 times.
  
• 
  19

  Mennecier, D., Saloum, T., Dourthe, P.M., Bronstein, J.A., Thiolet, C., Farret, O.

  Acute hepatitis after phytotherapy [2]
  (1999) Presse Medicale, 28 (18), p. 966. Cited 7 times.
  
• 
  20

  Vassiliadis, T., Anagnostis, P., Patsiaoura, K., Giouleme, O., Katsinelos, P., Mpoumponaris, A., Eugenidis, N.

  Valeriana hepatotoxicity
  (2009) Sleep Medicine, 10 (8), p. 935. Cited 8 times.
  doi: 10.1016/j.sleep.2008.09.009
  
• 
  21

  LIVERTOX®. VALERIAN (VALERIANA OFFICINALIS).
  (accessed on 18 December 2015)
  http://livertox.nih.gov/Valerian.htm
  

  •  
• 
  22

  Etogo-Asse, F., Boemer, F., Sempoux, C., Geubel, A.

  Acute hepatitis with prolonged cholestasis and disappearance of interlobular bile ducts following tibolone and Hypericum perforatum (St. John's wort). Case of drug interaction?
  (2008) Acta Gastro-Enterologica Belgica, 71 (1), pp. 36-38. Cited 6 times.
  
• 
  23

  Piccolo, P., Gentile, S., Alegiani, F., Angelico, M.

  Severe drug induced acute hepatitis associated with use of St John's wort (Hypericum perforatum) during treatment with pegylated interferon α
  (2009) BMJ Case Reports. Cited 2 times.
  http://casereports.bmj.com/content/2009/bcr.08.2008.0761.full?sid=1a2da049-1110-46ba-9717-47067eacdee0
  doi: 10.1136/bcr.08.2008.0761
  
• 
  24

  Promethazine-Summary of Product Characteristics.
  (accessed on 13 October 2015)
  http://www.medicines.org.uk/emc/medicine/15313/SPC/Phenergan+Elixir
  

  •  
• 
  25

  Vo, L.T., Chan, D., King, R.G.

  Investigation of the effects of peppermint oil and valerian on rat liver and cultured human liver cells
  (2003) Clinical and Experimental Pharmacology and Physiology, 30 (10), pp. 799-804. Cited 14 times.
  doi: 10.1046/j.1440-1681.2003.03912.x
  
• 
  26

  Anderson, I.B., Mullen, W.H., Meeker, J.E., Khojasteh-Bakht, S.C., Oishi, S., Nelson, S.D., Blanc, P.D.

  Pennyroyal toxicity: Measurement of toxic metabolite levels in two cases and review of the literature
  (1996) Annals of Internal Medicine, 124 (8), pp. 726-734. Cited 164 times.
  
• 
  27

  Bakerink, J.A., Gospe Jr., S.M., Dimand, R.J., Eldridge, M.W.

  Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants
  (1996) Pediatrics, 98 (5), pp. 944-947. Cited 78 times.
  
• 
  28

  Sullivan Jr., J.B., Rumack, B.H., Thomas Jr., H., Peterson, R.G., Bryson, P.

  Pennyroyal oil poisoning and hepatotoxicity
  (1979) Journal of the American Medical Association, 242 (26), pp. 2873-2874. Cited 65 times.
  doi: 10.1001/jama.242.26.2873
  
• 
  29

  Vallance, W.B.

  PENNYROYAL POISONING. A FATAL CASE
  (1955) The Lancet, 266 (6895), pp. 850-851. Cited 20 times.
  
• 
  30

  Yuen, M.-F., Tam, S., Fung, J., Wong, D.K.-H., Wong, B.C.-Y., Lai, C.-L.

  Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: A 1-year prospective study
  (2006) Alimentary Pharmacology and Therapeutics, 24 (8), pp. 1179-1186. Cited 43 times.
  doi: 10.1111/j.1365-2036.2006.03111.x
  
• 
  31

  Nam, H.K., Sun, H.H., Chun, H.J., Sang, K.L., Dong, W.L., Tae, W.J., Jae, S.L., (...), Tae, C.J.

  Pretreatment with 1,8-cineole potentiates thioacetamide-induced hepatotoxicity and immunosuppression
  (2004) Archives of Pharmacal Research, 27 (7), pp. 781-789. Cited 3 times.
  http://apr.psk.or.kr/home/journal/article_view.asp?articleuid={9AFE512A-13C6-446C-8A7E-87AE2DE67122}
  doi: 10.1007/BF02980149
  
• 
  32

  Xu, J., Hu, Z.-Q., Wang, C., Yin, Z.-Q., Wei, Q., Zhou, L.-J., Li, L., (...), Yin, L.-Z.

  Acute and subacute toxicity study of 1,8-cineole in mice
  (2014) International Journal of Clinical and Experimental Pathology, 7 (4), pp. 1495-1501. Cited 5 times.
  http://www.ijcep.com/files/ijcep1401056.pdf
  
• 
  33

  Davern, T.J., Chalasani, N., Fontana, R.J., Hayashi, P.H., Protiva, P., Kleiner, D.E., Engle, R.E., (...), Hoofnagle, J.H.

  Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury
  (2011) Gastroenterology, 141 (5), pp. 1665-1672. Cited 133 times.
  doi: 10.1053/j.gastro.2011.07.051
  
• 
  34

  Teschke, R., Frenzel, C., Wolff, A., Eickhoff, A., Schulze, J.

  Drug induced liver injury: Accuracy of diagnosis in published reports
  (2014) Annals of Hepatology, 13 (2), pp. 248-255. Cited 18 times.
  http://www.annalsofhepatology.com/numeros/2014/ah142_march-abril_v13_n2_2014/pdfs/12_142_v13n2_2014_DrugInduced.pdf
  
• 
  35

  Teschke, R., Frenzel, C., Schulze, J., Eickhoff, A.

  Suspected herbal hepatotoxicity: The pharmacovigilance dilemma with disputed and obsolete evaluation methods
  (2012) Regulatory Toxicology and Pharmacology, 64 (2), pp. 343-344. Cited 10 times.
  doi: 10.1016/j.yrtph.2012.06.010
  
• 
  36

  Douros, A., Bronder, E., Andersohn, F., Klimpel, A., Thomae, M., Ockenga, J., Kreutz, R., (...), Garbe, E.

  Drug-induced acute pancreatitis: Results from the hospital-based Berlin case-control surveillance study of 102 cases
  (2013) Alimentary Pharmacology and Therapeutics, 38 (7), pp. 825-834. Cited 6 times.
  doi: 10.1111/apt.12461
  
• 
  37

  Garbe, E., Andersohn, F., Bronder, E., Klimpel, A., Thomae, M., Schrezenmeier, H., Hildebrandt, M., (...), Kurtal, H.

  Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study
  (2011) British Journal of Haematology, 154 (5), pp. 644-653. Cited 21 times.
  doi: 10.1111/j.1365-2141.2011.08784.x
  
• 
  38

  Criteria of drug-induced liver disorders. Report of an International Consensus Meeting
  (1990) Journal of Hepatology, 11 (2), pp. 272-276. Cited 721 times.
  doi: 10.1016/0168-8278(90)90124-A
  
• 
  39

  Teschke, R., Wolff, A., Frenzel, C., Schwarzenboeck, A., Schulze, J., Eickhoff, A.

  Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment
  (2014) World Journal of Hepatology, 6 (1), pp. 17-32. Cited 32 times.
  http://www.wjgnet.com/1948-5182/pdf/v6/i1/17.pdf
  doi: 10.4254/wjh.v6.i1.17
  

  Douros, A.; Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Germany; email:antonios.douros@charite.de
© Copyright 2016 Elsevier B.V., All rights reserved.