HERBALS AND DIETARY SUPPLEMENTS
Herbals and Dietary Supplements
Herbal and dietary supplements (HDS) are commonly used by many people, both healthy and with specific ailments. The “well” HDS user often seeks to preserve health or promote a healthier lifestyle. The ailing HDS user seeks to supplement conventional therapies, hoping to achieve better health, or even to substitute for prescribed medications, with the perception that HDS are safe and as effective. It is estimated that over 40% of the U.S. population uses alternative therapies of some kind, most commonly HDS. Up to 40% of patients attending liver clinics also use supplements. Alarmingly, however, most patients who use HDS do not reveal this to their primary care provider. Moreover, it is not uncommon for providers to fail to ascertain a history of HDS use from their patients. Users of HDS tend to be Asians, younger, highly educated, and more health conscious than nonusers. The most common reasons for their use include obesity/weight loss, body building, menopausal symptoms, gastrointestinal disorders such as indigestion or constipation, liver disease, and neurological complaints such as headache and migraines.
Herbal and dietary supplements are considered foods, and are defined as products taken by mouth that contain a dietary ingredient intended to supplement the diet. These ingredients include vitamins, minerals, herbs and other botanicals, amino acids, enzymes, organ tissues, and metabolites. However, since HDS are not drugs, they are regulated differently than conventional pharmaceuticals. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA) (http://www.fda.gov/Food/DietarySupplements/default.htm), manufacturers of HDS are responsible for the safety of their products, but need not have FDA approval before marketing. More recently, the Current Good Manufacturing Practices–Dietary Supplement Act (2007)–establishes the minimum standards for manufacturing, packaging, labeling, and holding, and is intended to ensure the identify, purity, quality, strength, and composition. Manufacturers are not required to conduct preclinical safety and efficacy assessments prior to marketing. The FDA’s specific responsibility is to determine if an HDS is unsafe, after which it can take action to recommend withdrawal from the market. Concern over a specific HDS or ingredient usually is triggered from reports of adverse events which may come from MEDWATCH or the manufacturer, which is statutorily compelled to alert the FDA of such events about which it becomes aware.
The hepatotoxic potential of HDS has been recognized for many years. There are no reliable population-based statistics for the incidence of toxicity attributable to HDS in the United States, although the true incidence is likely to be very low. In the Drug Induced Liver Injury Network, HDS were implicated in approximately 10% of cases, but this rate appears to be increasing and most recently was more than 16% of cases. As discussed in the various HDS records within LiverTox, many single herbs have been implicated in liver toxicity. However, most currently available HDS comprise complex mixtures of ingredients and, although the FDA requires that a product label accurately reflect the contents, reports exist of product contamination and unlabeled ingredients. Reported contaminants include heavy metals, pharmaceuticals, microbial products, and pesticides. Further, HDS are vulnerable to variation in the quality or strength of ingredients, depending upon the time and conditions of harvest, as well as the part of the plant that is used for the product (for instance, leaf vs root vs. stem). Finally, analytical phytochemistry of HDS products implicated in causing liver injury often reveals adulteration of the product and sometimes mislabeling and absence of the botanical listed on the label and presence of a related or unrelated herbal that may be the hepatotoxic agent.
The diagnosis of HDS associated liver injury is predicated upon the usual principles of causality assessment, including establishing a chronology which implicates the HDS as having been taken before the onset of injury, exclusion of other causes of liver disease, and the response to withdrawal. The published experience with HDS associated liver toxicity is growing, but limited for many of the myriad available products. As in conventional pharmaceuticals, the confidence with which a diagnosis of liver injury is made depends, to a great extent, on the number of previously reported and published cases. Thus, time and experience will lead to more precise attribution of liver injury to HDS. Even for those HDS in which significant published experience on toxicity exists, the attribution of injury to a specific ingredient of the HDS is difficult, due to the complexity of the mixture. Arguably, the most surmountable obstacles to diagnosing HDS associated liver injury include the provider’s foresight in obtaining a complete supplement use history and the patient’s willingness to disclose their use.
Finally, chemical analysis of the implicated product can be very valuable in assigning causality, particularly for botanicals that have not been commonly implicated in causing liver disease as such analysis may identify the presence of a well established hepatotoxic agent. Examples of contaminants found in herbal preparations include germander in products labeled as being skullcap and various Asian Actaea in products labeled as black cohosh.
Mechanism of Injury
The mechanism of liver injury due to HDS is, in the majority of cases, unknown. Most cases appear to be idiosyncratic and the clinical picture, including histology, is no different than that which is seen in conventional drug associated liver injury. However, some HDS are associated with a specific type of injury; for example, pyrrolizidine alkaloids which have been reported to lead to sinusoidal obstruction syndrome. As learned through the experience of the Drug Induced Liver Injury Network, it appears that most patients who sustain liver injury attributable to HDS manifest a hepatocellular pattern of injury.
Outcome and Management
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Herbals and Dietary Supplements
17 March 2014
Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 731-4. (Single author review of hepatotoxicity published in 1999; herbal medications covered in 3 pages at the end of a chapter on miscellaneous drugs, focusing on pyrrolizidine containing preparations, Chinese herbs, germander, chaparral, valerian, skullcap, amanita, and pennyroyal).
Liu LU, Schiano TD. Hepatotoxicity of herbal medicines, vitamins and natural hepatotoxins. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 733-54. (Review of hepatotoxicity published in 2007; HDS are covered in a 22 page chapter).
Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary
supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd
ed. Amsterdam: Elsevier, 2013, pp. 631-58. (Review of hepatotoxicity of
herbal and dietary supplements [HDS] published in 2013; HDS are covered in a 26 page chapter).
Larrey D. Hepatotoxicity of herbal remedies. J Hepatol 1997; 52: 97-103. PubMed Citation (Review of hepatotoxicity of herbals focusing upon pyrrolizidine alkaloids, germander and Chinese herbal medications).
Stickel F, Egerer G, Seitz HK. Hepatotoxicity of botanicals. Public Health Nutr 2000; 3: 113-24. PubMed Citation (Review of hepatotoxicity of botanicals with specific discussion of Chinese herbals, germander, pyrrolizidine alkaloids, chaparral, and mushroom poisoning).
Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22: 195-206. PubMed Citation (Review of HDS hepatotoxicity and description of patterns of liver injury, including discussion of clinical patterns, potential risk factors, and herb-drug interactions with specific discussion of pyrrolizidine alkaloids, germander, Chinese herbs, chaparral, greater celandine, pennyroyal, herbal laxatives, and kava).
De Smet PA. Herbal remedies. N Engl J Med 2002; 347: 2046-56. PubMed Citation (Brief review of herbal remedies discussing their growing use, lack of regulation, problems of variability in content, quality, safety, potential adulterants and adverse events including hepatotoxicity, efficacy and special needs for prospective randomized controlled trials to define these factors; specific discussion of hawthorn, saw palmetto, gingko and St. John's Wort).
Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003; 7: 453-73. PubMed Citation (Review of HDS associated hepatotoxicity, including common patterns of presentation and specific discussion of pyrrolizidine alkaloids, chaparral, germander, pennyroyal, skullcap, valerian, kava, Chinese herbals, greater celandine, and Lipokinetix).
Pittler MH, Ernest E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther 2003; 18: 451-71. PubMed Citation (Systematic review of published cases of hepatotoxicity due to herbal medications listing 52 case reports or case series, most common agents being celandine , chaparral , germander , Jin Bu Huan , kava , Ma Huang , pennyroyal oil , skullcap , Chinese herbs , valerian ).
Pak E, Esrason KT, Wu VH. Hepatotoxicity of herbal remedies: an emerging dilemma. Prog Transplant 2004; 15: 91-6. PubMed Citation (Review of hepatotoxicity of herbal medications stressing the recent rise in numbers of cases, with literature review of comfrey, chaparral, germander, Ma Huang, Jin Bu Huan, greater celandine, cascara, kava and St. John’s wort).
Myers SP, Cheras PA. The other side of the coin: safety of complementary and alternative medicine. Med J Aust 2004; 181: 222-5. PubMed Citation (Review of hepatotoxicity of herbal medications discussing their rising use in Australia and the problems of quality and safety, separating adverse events into "predictable" reactions and "idiosyncratic" reactions and stressing the need for further research, regulation and patient education).
Lenz TL, Hamilton WR. Supplemental products used for weight loss. J Am Pharm Assoc 2004; 44: 59-67. PubMed Citation (At least 50 herbal and dietary supplements have been promoted for weight loss, but none have strong clinical evidence of efficacy and several are toxic [ephedra and green tea]).
Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, including 7 [5%] for herbal medications).
Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005; 43: 901-10. PubMed Citation (Topical review, highlighting Chinese herbs, pyrrolizidine alkaloids, germander, greater celandine, kava, and chaparral, among others; insights on diagnosis and management are offered).
Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005; 129: 512-21. PubMed Citation (Reports of drug induced liver injury to a Spanish network: among 570 cases, herbal medications accounted for 9 [1.5%]).
Seeff LB. Herbal hepatotoxicity. Clin Liver Dis 2007; 11: 577-96. PubMed Citation (Review of HDS associated hepatotoxicity, with review of the literature and details of hepatic injury for black cohosh, chaparral, Chinese herbs, comfrey and pyrrolizidine alkaloids, germander, celandine, kava, mistletoe, pennyroyal, skullcap and valerian).
García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. PubMed Citation (Among 521 cases of drug induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals, including green tea extracts in 3, cascara in 2, and horse chestnut, copalchi, chitosan, senna, valerian, kava, phytosoy and biosoy in 1 case each).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbals and dietary supplements, prominent agents being green tea, androgenic steroids, and miscellaneous Hydroxycut and Herbalife products).
Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-82. PubMed Citation (Review of the problems of causality assessment in herbal and dietary supplement [HDS] associated liver disease, including the variable clinical presentations, the complexity and lack of information on their components, absence of controlled trials demonstrating safety and efficacy, the possibility of contamination or incorrect labeling and frequent underreporting of herbal use by patients. The regulation of HDS is under DSHEA which requires manufacturers to determine safety and prohibits claims of efficacy in treating specific diseases. The US Pharmacopeia sets standards for food and drugs, and includes HDS; HDS induced liver injury is a growing problem and current accounts for at least 10% of cases of acute liver injury due to medications).
Jacobsson I, Jönsson AK, Gerdén B, Hägg S. Spontaneously reported adverse
reactions in association with complementary and alternative medicine substances
in Sweden. Pharmacoepidemiol Drug Saf 2009; 18: 1039-47. PubMed Citation
(Review of 778 spontaneous reports of adverse reactions to herbals to Swedish Registry found 31 with increased liver enzymes, 26 with elevated aminotransferase levels, 22 with mixed liver reaction and 12 with hepatitis; agents implicated in causing liver injury included valerian, ginseng, green tea, and aloe vera).
Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute
liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;
52: 2065-76. PubMed Citation (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 12 [9%] were due to herbals, including several herbal mixtures, usnic acid, Ma Huang, black cohosh, and Hydroxycut products).
Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver Int 2011; 31: 595-605. PubMed Citation (Review of current understanding of liver injury from herbals and dietary supplements focusing upon Herbalife and Hydroxycut products, green tea, usnic acid, noni juice, Chinese herbs, vitamin A and anabolic steroids).
Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a
tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. PubMed Citation (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, herbal drugs and supplements, and a discussion of the difficulties of causality attribution and appeal for publications to be more complete in presenting information on the liver injury and its link to herbal preparations).
Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement
hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3-17. PubMed Citation (Systematic review of literature on HDS associated liver injury with specific discussion of Ayurvedic products, chaparral, Chinese herbals, germander, greater celandine, green tea, Herbalife and Hydroxycut products, kava, pennyroyal oil, pyrrolizidine alkaloids and herb-drug interactions).
Internet searches will identify hundreds of websites with information on specific botanicals and nutritional supplements, but the quality of the information varies enormously and many websites offer only anecdotal and unreliable testimonies to the benefits and offers for sale of the HDS. Fairly reliable and unbiased information on HDS can be obtained from the following US Government supported websites.
www.ods.od.nih.gov (The health information website of the Office of Dietary Supplements in the Office of the Director, National Institutes of Health)
www.nccih.nih.gov/health/supplements/wiseuse.htm (Information website of the National Center for Complementary and Integrative Health, National Institutes of Health)
www.nlm.nih.gov/medlineplus/druginfo/herb_All.html (Website of the National Library of Medicine’s MedlinePlus)