Invited reviewLiver toxicity related to herbs and dietary supplements: Online table of case reports. Part 2 of 5 series
Introduction
This is the second of five review articles investigating dietary supplements (DS; includes herbs): Article one covers DS definitions, usage, efficacy and safety, and an overview of DS regulation in the United States (Brown, 2017a); and articles two through five cover case reports in tabular form related to liver toxicity, kidney toxicity, cardiotoxicity, and cancer published in the medical literature (Brown, 2017b, Brown, 2017c, Brown, 2017a, Brown, 2017b). Interest in complementary and alternative medicine (CAM), also known as functional, integrative, traditional, or holistic medicine, continues to grow, but “natural” is not always safe. Although the majority of botanical products appear inherently safe (Marcus and Grollman, 2002), and some have demonstrated efficacy, this review focuses on the potentially life-threatening dietary supplements that increase liner injury risk as detected through PubMed case reports. Case reports do not always demonstrate causation or association, but reoccurrences raise concerns (Haaz et al., 2006).
In this review, the characteristics and prevalence of liver injuries are defined, the literature search methods employed are described, and a summary table of the results along with a brief discussion of selected DS are presented.
Section snippets
DILI versus DSLI
The equivalent of drug-induced liver injury (DILI), which is caused by drugs, is herb- and DS-induced liver injury (DSILI; previously described as HILI, which only covers herbs and thus excludes many products in the broader DS category). The vast majority of pharmaceuticals have beneficial effects, but adverse events (AE) or serious adverse events (SAE) related to either drugs or DS do occur, though they are rare events. Because the liver is responsible for eliminating toxins from the body, it
Risk factors for liver injury
As discussed below, factors that increase the risk for DILI or DSILI include older age, female gender, higher dose, malnutrition, alcoholism, genetics, race, concomitant drugs, and underlying disease (Andrade et al., 2008; Chalasani, 2010). To predict DILI risk for specific drugs in development, the DILIsym® software program (www.dilisym.com) and the Mechanism Based Integrated System of using in vitro assays (www.pip-dili.eu) can be used.
Causality scoring systems
DILI or DSILI diagnosis is primarily a process of elimination based on mathematical probability (Garcia-Cortes, 2011). Expert opinion remains the gold standard, with a physician reviewing the patient's history, blood test results, hepatobiliary imaging, and, possibly, liver biopsy results (Chalasani et al., 2014). After a liver injury is clearly diagnosed, the cause is pinpointed through any of several methods divided into three categories: (1) expert opinion, (2) probabilistic approaches,
Treatment of DILI
DILI treatment consists of immediately withdrawing the responsible medication; many patients start to improve within hours or days (Chalasani et al., 2014). In one study, most of the 70 patients, with elevated liver enzymes and a normal liver biopsy, recovered (Strasser et al., 2015). However, approximately 14% go on to develop chronic liver disease (Chalasani et al., 2014). DILI from antidepressants may be irreversible (Voican et al., 2014). A minority of patients experience acute liver
Prevalence of DILI and DSILI in North America & Europe
DILI cases, whether they are caused by drugs or DS, are not tracked through annual surveillance. DILI is rare for most drugs, occurring in approximately one per 10,000–1,000,000 persons exposed (Fontana et al., 2010). However, epidemiologic data suggest that the rate might be as high as 20 DILI cases per 100,000 people exposed in Western countries (Leise et al., 2014). The prevalence of DILI is largely unknown, as hospitals and liver centers do not appear to have similar causality
DILI and DSILI prevalence in Asia, Africa, South America, and other areas
A real concern is the apparently higher rate of DSILI in certain countries, especially in areas where traditional medicine is an integral part of society that has been practiced for thousands of years.
After Ayruvedic (Indian) medicine, one of the oldest traditions of herbal medicine originated in China, where it was practiced for thousands of years BC (Stickel and Shouval, 2015). Attributing liver injuries to a particular Chinese herb is difficult because Traditional Chinese Medicine (TCM)
Creating DS Toxic Tables
An online “DS Toxic Table” providing a summary of potentially life-threatening, hepatotoxic DS based on a thorough review of PubMed case reports has been previously unavailable in the United States. The goal of this research review was to create a “Toxic Table” summarizing the DS case reports reported in PubMed associated with liver injuries.
LiverTox.nih.gov does list selected drugs and DS associated with liver injuries, but the list is not yet complete, herbs not associated with liver injuries
Methods: literature search
Documented PubMed case reports (1966 to June, 2016, and cross-referencing) of DS appearing to contribute to liver toxicity were listed in “DS Toxic Tables.” The broad search included the keywords of “plant extracts” or “plant preparations” with “liver toxicity” and “toxicity” [“human” species always checked]. The narrowed search included the keywords of “herb” or “dietary supplement” (combined with “liver” to generate an overview list, and possibly “toxicity” to narrow the selection. Specific
Results: DS-Related liver injuries
Approximately 21 herbs were related to liver injury case reports that include, but are not limited to: aloe vera (Aloe barbadensis), arrowroot juice (Maranta arundinacea & others?), black cohosh (Actaea racemosa), cascara (Cascara sagrada), celandine (Chelidonium majus L.), chaparral (Larrea divaricate), comfrey (Symphytum officinale), fo-ti (Polygonum multiforum), gota kolu (Centella asiatica), green tea extract (Camellia sinensis), groundsel (Senecio vulgaris), Hathisunda (Heliotropium
Herb-related liver injuries
Over the last 50 + years (1966–2015), approximately 21 herbs have been reported in PubMed to be associated with liver toxicity in case report publications. Although the number of publications does not always reflect the number of case reports, the herbs with the highest number of publications (not cases), in descending order, were (number in the last 10 years is in parentheses):Herb Total Publications (Per year) Status Germander (Teucrium chamaedrys L.) – 23 (7) No longer sold Black cohosh (Actaea
A balanced perspective
This review reveals that over the past 50 years, only approximately 21 herbs (minus germander and usnic acid) and 12 DS (minus the nine no longer sold) posed a possible risk for liver injures in certain individuals. Vitamin A and niacin were on the list due to excessive intake (a disqualifying criteria), and it should not be forgotten that these are known liver toxins at high doses. The list would be slightly longer if Chinese herbs were included, but this was a difficult task given that these
Current regulations
The FDA, Federal Trade Commission, Attorneys General Office, and Department of Justice work to protect the public from DS-related liver injuries (Brown, 2017a). As a result, almost one third of the DS in this review table are no longer sold (indicated by shaded DS in Table 3, Table 4).
Clustered cases should, but sometimes do not, receive immediate attention. Before calling for stricter DS regulations, however, one should consider the likely effectiveness of this approach. If stringent FDA
Limitations
The “DS Toxic Tables” in this review series are based on the PubMed indexing of peer-reviewed scientific journal articles and while comprehensive, are not entirely inclusive of all the literature, nor should it be viewed as such. Limiting the literature review to this resource ensures some degree of standardization. This review did not cover literature indexing resources of other countries or regions that may have more varied histories or usage of DS (including herbs) as part of their
Additional case reports
The case reports presented here do not reflect all the case reports in the literature, so additional case report submissions, pre-existing or new, are welcomed online. The author is available to assist in writing up case reports for publication, after which the data will be added to the (http://mscr.hawaii.edu/faculty/amybrown/) online table.
DS Toxic tables for proactive protection
These continuously updated online DS Toxic Tables can now be accessed by consumers, clinicians, and corporations to find DS and/or their ingredients that have been reported to be related to toxicity. If a DS is related to toxicity cases, regardless of how small due to idiosyncratic DS reactions, then why impart the risk to the consumer or corporation? The DS ingredients listed in these tables may need further consideration by government agencies, DS companies, manufacturers, distributors, and
Bullet summary
Herbs
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Approximately 21 herbs have been related to liver injury case reports (1966–July, 2016). Germander and usnic acid are no longer sold in the United States.
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The next three most prominent offenders (black cohosh, kava, and green tea extracts) may need warning labels.
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USP accepts black cohosh into USP Compendia Category A, but with labeled warnings. Discontinue use with symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice.
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USP did not admit kava into USP-NF monograph
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Conflict of interest/Caveat
Amy Brown is CEO of Natural Remedy Labs, LLC, and has served as an expert witness in herb and DS cases. The names, formulations and corporate name and/or ownership of DS may change, so any identification in this publication may no longer apply.
References (349)
- 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) - et al.
Comfrey herb tea-induced hepatic veno-occlusive disease
Am. J. Med.
(1989) A case for immediate-release niacin
Heart Lung
(2012)- et al.
Acute hepatitis induced by greater celandine (Cheliodonium majus)
Gastroenterology
(1999) - et al.
Hepatitis after chronic abuse of senna
Lancet
(1991) Fulminant exacerbation of autoimmune hepatitis after the use of ma huang
Am. J. Gastroenterol.
(2001)An overview of herb and dietary supplement efficacy, safety, and regulations in the United States with suggested improvements. Part 1 of 5 Series
Food Chem Toxicol.
(2017)Liver toxicity related to herbs and dietary supplements: online table of case reports. Part 2 of 5 series
Food Chem Toxicol.
(2017)Kidney toxicity related to herbs and dietary supplements: online table of case reports. Part 3 of 5 series
Food Chem Toxicol.
(2017)- et al.
Kava-induced acute icteric hepatitis
Gastroenterol. Hepatol.
(2002)
Risk factors for idiosyncratic drug-induced liver injury
Gastroenterology
Hepatic sinusoidal-obstruction syndrome: toxicity of pyrrolizidine alkaloids
J. Hepatol.
Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice
Food Chem. Toxicol.
Severe acute hepatitis associated with intake of Aloe vera tea
Gastroenterol. Hepatol.
Gotu Kola induced hepatotoxicity in a child - need for caution with alternative remedies
Dig. Liver Dis.
Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen
Life Sci.
Eighteen cases of liver injury following ingestion of Polygonum multiflorum
Complement. Ther. Med.
Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity
J. Hepatol.
Mechanism of hepatotoxicity due to black cohosh (Cimicifuga racemosa): histological, immunohistochemical and electron microscopy analysis of two liver biopsies with clinical correlation
Exp. Mol. Pathol.
A case of hepatotoxicity caused by green tea
Free Radic. Biol. Med.
Acute hepatitis induced by Camellia sinensis (green tea)
An Med Interna
Hepatic injury in 12 patients taking the herbal weight loss AIDS Chaso or Onshido
Ann Intern Med.
Cholestatic hepatitis after ingestion of chaparral leaf: confirmation by endoscopic retrograde cholangiopancreatography and liver biopsy
Am. J. Gastroenterol.
Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature
Ann. Intern Med.
Idiosyncratic drug hepatotoxicity: a 2008 update
Expert Rev. Clin. Pharmacol.
Energy drinks: another red flag for the liver allograft
Liver Transpl.
Revisiting acute liver injury associated with herbalife products
World J. Hepatol.
Acute liver injury associated with a newer formulation of the herbal weight loss supplement Hydroxycut
BMJ Case Rep.
Review article: drug-induced liver injury–its pathophysiology and evolving diagnostic tools
Aliment. Pharmacol. Ther.
The irony of herbal hepatitis. Ma-huang-induced haptotoxicity associated with compound heterozygosity for hereditary hemochromatosis
Dig. Dis. Sci.
Effects of Cissus quadrangularis on goats and sheep in Sudan
Rev. Elev. Med. Vet. Pays Trop.
International Psoriasis Council. Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic
J. Eur. Acad. Derm. Venereol.
Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants
Pediatrics
Toxic hepatitis induced by Polygonum multiflorum
Vnitr Lek.
Chaparral-induced hepatic injury
Am. J. Gastroenterol.
Several cases of liver affected by aloe vera
Lakartidningen
Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis)
Ann. Intern Med.
Chronic active hepatitis and cirrhosis induced by wild germander. 3 cases
Gastroenterol. Clin. Biol.
Linoleic acid induced acute hepatitis: a case report and review of the literature
Case Rep. Hepatol.
Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland
Gastroenterology
Oral aloe vera-induced hepatitis
Ann. Pharmacother.
Acute liver failure after administration of herbal tranquilizer kava-kava (Piper methysticum)
J. Clin. Psychiatry
Three new herbal hepatotoxic syndromes
J. Toxicol. Clin. Toxicol.
Heart toxicity related to herbs and dietary supplements: online table of case reports. Part 4 of 5 series
Food Chem Toxicol.
Cancer related to herbs and dietary supplements: online table of case reports. Part 5 of 5 series
Food Chem Toxicol.
Review article: herbal and dietary supplement hepatotoxicity
Aliment. Pharmacol. Ther.
Role of nutrition in the drug-metabolizing enzyme system
Pharmacol. Rev.
Renal and hepatic injuries in human intoxication with Atractylis gummifera
Nefrologia
Inpatient admissions for drug-induced liver injury: results from a single center
Dig. Dis. Sci.
Vitamin A toxicity in a physical culturist patient: a case report and review of the literature
Ann. Hepatol.
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