Download PDF
Semin Liver Dis 2009; 29(4): 373-382
DOI: 10.1055/s-0029-1240006
© Thieme Medical Publishers

Herbal and Dietary Supplement Hepatotoxicity

Victor J. Navarro1
  • 1Professor of Medicine, Pharmacology and Experimental Therapeutics, Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, Pennsylvania
Further Information

Victor J NavarroM.D. 

Professor of Medicine, Pharmacology and Experimental Therapeutics, Division of Gastroenterology and Hepatology, Thomas Jefferson University

132 S. 10th Street, Suite 480 Main Building, Philadelphia, PA 19107

Email: victor.navarro@jefferson.edu

Publication History

Publication Date:
13 October 2009 (online)

 PDF Download Permissions and Reprints
Table of Contents #

ABSTRACT

Herbal and dietary supplements (HDS) are commonly used in the United States and throughout the world. The Dietary Supplement Health and Education Act and public standards set through the U.S. Pharmacopeia provide regulatory framework for these products. These regulations help to ensure the safety of grandfathered and new HDS coming onto the market, and the opportunity to identify and take action against unsafe products that have been distributed. The clinical patterns of presentation and severity of HDS-associated hepatotoxicity can be highly variable, even for the same product. In addition, accurate causality assessment in cases of suspected HDS hepatotoxicity is confounded by infrequent ascertainment of product intake by healthcare providers, under-reporting of HDS use by patients, the ubiquity of HDS and the complexity of their components, and the possibility for product adulteration. Additional measures to prevent HDS-induced hepatotoxicity include greater consumer and provider awareness, increased spontaneous reporting, and reassessment of regulations regarding the manufacturing, distribution, and marketing of these products.

#

KEYWORDS

Hepatotoxicity - herbal dietary supplements - Dietary Supplement Health and Education Act (DSHEA) - U.S. Pharmacopeia (USP)

A discussion of hepatotoxicity attributable to herbal and dietary supplements (HDS) is inextricably linked to the topic of drug-induced liver injury (DILI) due to prescription and over-the-counter medications. There is great overlap in the clinical presentation, spectrum of disease, and causality assessment in HDS and DILI cases. However, the ubiquitous use of HDS in the face of under-reporting to healthcare providers,[1] the complexity and variability of products, and the lack of uniform compliance by manufacturers with regulations make HDS-associated hepatotoxicity uniquely challenging for clinicians. The purpose of this article is to address the salient features of liver injury attributable to HDS, including an assessment of the regulatory framework that governs their use, patterns of presentation with recent examples of HDS-associated hepatotoxicity, challenges in diagnosis, and potential preventative measures.

Congress defined a dietary supplement in the Dietary Supplement Health and Education Act (DSHEA) of 1994 as a product intended to supplement the diet, taken by mouth, and that contains any of the following ingredients: vitamins, minerals, herbs or other botanicals, and extracts or concentrates thereof.[2] The use of HDS in the United States has dramatically risen over the past two decades; in 2004, 18.9% of U.S. adults reported using natural products, which is nearly double of that reported in 1999.[3] [4] [5] In addition, an estimated $4 billion was spent in 1998 on herbal medicines,[6] a figure likely to be much higher now. In a secondary analysis of the 2002 National Health Interview Survey, it was found that most Americans perceive HDS as important to their health.[1] Rates of HDS use are higher for women, adults between 45 and 64 years of age, and those with higher levels of education. Use was lower among whites and blacks compared with Asians and Native Americans. Importantly, only a third of HDS consumers reported their use of these products to a healthcare provider.[1]

Several factors likely contribute to the frequent use of HDS.[7] These include their perceived effectiveness, safety, accessibility, and affordability, as well as patient dissatisfaction with conventional medical practice and limitations in medical knowledge. Furthermore, the use of HDS must be viewed in a cultural context, as herbal medicine is deeply entrenched in many Asian societies.[8] Arguably, obesity is one of the strongest driving forces for use of HDS in the United States, despite recommendations to the contrary due to concerns of safety and lack of efficacy.[9] Blanck and colleagues found that the prevalence of HDS use for weight loss was 15.2% among U.S. residents and that nearly 1 in 10 users had consumed supplements for more than a year.[10]

#

THE REGULATORY FRAMEWORK FOR HDS

The DSHEA of 1994,[2] an amendment to the U.S. Federal Food, Drug, and Cosmetic Act (FD&C), currently governs the regulation of HDS in the United States. This act allows products that were already in distribution before implementation and still considered safe to remain on the market, pending information to the contrary. In addition, the burden of proof regarding potential safety concerns falls on the U.S. Food and Drug Administration (FDA) after a product has been marketed. The DSHEA requires the manufacturer to determine the safety of the HDS product before marketing and also to ensure that claims made about the product are accurate and not misleading. However, the manufacturer is not bound to register itself or its product before distribution, and there are no aspects of the law that give the FDA authority to review and approve HDS products for safety or effectiveness. It is only when a manufacturer introduces a new dietary ingredient that a premarket review for safety data is required by law; otherwise, a manufacturer has no obligation to the FDA. Regulations require that the label of a dietary supplement contain certain information, including a complete list of ingredients, as well as the identity of the manufacturer. If a product label claims to affect a body function, claims to affect general well being, or indicates a benefit related to a nutrient deficiency, the product must bear a disclaimer noting that the product was not evaluated by the FDA and is not intended to diagnose, treat, cure, or prevent disease.[11]

The spirit of the DSHEA is to strike a balance between permitting the FDA to take action against products with misrepresented claims or safety concerns and allowing convenient and broad access to HDS for the general public.[12] An important step toward better protecting the safety of consumers using HDS came in 2007, as the Final Rule for Current Good Manufacturing Practices (cGMPs) for Dietary Supplements.[13] This rule requires certain procedures in production of HDS that verify contents and freedom from contamination. Table [1] conveys salient points of these key regulatory milestones.

Table 1 Regulatory Milestones for Herbal and Dietary Supplements
Milestones Year Key Points
Dietary Supplement Health and Education Act (DSHEA) 1994 • Defines dietary ingredients as vitamins, minerals, herbs, amino acids (and any concentrate, metabolite, extract thereof)
• Allows the use of the USP–National Formulary monographs as reference standards
• Identifies products as misbranded if found to not conform with USP standards but claims to do so
• Makes conformity with USP voluntary
• Assigns no responsibility for safety surveillance or reporting to manufacturer
Final Rule for Dietary Supplement Current Good Manufacturing Practices (cGMPs) 2007 • Provides standards in identification, purity, strength, composition, and purity of the final dietary supplement
• Does not focus on the inherent safety of the ingredients used
• Contains no minimum requirement for quality
#

UNITED STATES PHARMACOPEIA

The United States Pharmacopeia (USP) is the organization that sets standards for food and drugs in the United States.[14] The USP–National Formulary is named by the DSHEA as its official compendia of monographs for HDS, and it is a vital component of their regulatory framework. The USP is also recognized by many countries around the world.[15] Through its monographs, the USP promulgates standards and verification programs for manufacturers to assure the quality of dietary supplements and ingredients. The USP–National Formulary monographs not only contain requirements for packaging, labeling, and testing, but also contribute useful information to patients and practitioners, as evidenced by the systematic reviews of HDS available in the published medical literature. However, manufacturers of HDS may voluntarily claim conformity with standards of the monograph alluding to their product in the USP–National Formulary. The importance of conformity is that failure to adhere to standards as published in the respective HDS monograph may result in adverse action by the FDA. Based on a review of the available safety data for an HDS, the USP determines whether admission to the compendia and creation of a monograph is appropriate for any given dietary ingredient. Table [2] lists the USP Revised Admission Criteria.

Table 2 United States Pharmacopeia (USP) Revised Admission Criteria and Safety Classification for Dietary Supplements
Class A • Admitted to the compendia
• Available evidence[*] does not indicate a serious risk to health[†] that would preclude a monograph
• After conducting safety reviews, findings and recommendations are disseminated through publications
• Supplements in class with labeled warnings of or related to hepatotoxicity:
 ˆ Black cohosh
 ˆ Licorice
Class B • Not admitted into the compendia
• Available evidence indicates serious risk to health
• Supplements in class:
 ˆ Kava[‡]
 ˆ Ephedra
For further information see: http://www.usp.org/USPNF/notices//USPRevisedAdmissionCriteria.html.

1 Available evidence that the USP Expert Committees base decisions include but is not limited to human data from clinical studies, adverse event reports, preclinical data, and historical use.

2 Serious risk to health may include death, life-threatening experience, inpatient hospitalization, persistent disability or incapacity, congenital anomaly, or birth defect.

3 Reports of Kava-associated hepatotoxicity[72] [113] [114] led to its being designated as not suitable for admission into the USP Compendia, due to safety concerns.

The approach to regulation of HDS is different in the European Union.[16] Regulations enacted over the past 10 years permit use of published literature in support of safety and efficacy claims. In addition, several criteria have been set that allow herbal medicines to be approved for use, including: a long track-record of safe use, indications that do not require supervision by a healthcare provider, and specified dosing instructions.[17]

Given the regulatory environment that permits voluntary conformity to USP standards, product adulteration is an unavoidable risk. This may come in the form of heavy metal or microbial contamination and undeclared ingredients, either botanical or pharmaceutical. The presence of adulterants in herbal medicines has been reported repeatedly.[18] [19] [20] [21] [22] In one notable study, 7% of 243 Asian medicines collected from California herbal shops contained undeclared pharmaceuticals, including ephedrine, chlorpheniramine, methyltestosterone, and phenacetin. When combined with the products that contained undeclared heavy metals, including lead, arsenic, and mercury, 32% of the products analyzed were adulterated.[18] Recognizing the observation of Stickel et al,[23] the notion of HDS adulteration deserves further study.

#

EPIDEMIOLOGY OF HDS-ASSOCIATED HEPATOTOXICITY

The widespread availability of HDS and the low frequency with which patients report their use[1] means that the true frequency of attributable hepatotoxicity is unknown. Moreover, current regulations do not mandate surveillance or reporting of nonserious adverse events by the manufacturer to the FDA. Therefore, any estimates of the prevalence or incidence of HDS-associated hepatotoxicity are likely to be falsely low. Notwithstanding this limitation, an assessment of the frequency of injury from HDS compared with prescribed medications can be determined through various means. In one prospective study of 22 Singaporean patients with DILI, HDS were implicated in 15 (68%).[24] In contradistinction to this experience, the U.S. Drug-Induced Liver Injury Network (DILIN) prospective study found HDS to be implicated in ∼10% of consecutively enrolled cases.[25] In another U.S. study, 7 of 20 (35%) cases of acute liver failure (ALF) referred for liver transplant surgery in 2001 and 2002 had HDS as the only identifiable cause for liver disease.[26] Furthermore, in a Spanish registry of DILI, 2% of 531 cases of DILI were attributed to herbal remedies or dietary supplements.[27]

There are no population-based studies in the United States that give insight into the incidence of liver injury among patients who use HDS. In a Chinese study of 1507 consecutive inpatients treated with traditional Chinese medicine, 0.9% developed more than a twofold elevation of serum alanine aminotransferase (ALT) levels, but only two patients were symptomatic.[28] In a smaller study of patients taking herbal medicine in Korea, no increase in the frequency of liver biochemical abnormalities was found.[29] Whether global variation in frequency statistics is a phenomenon of different reporting mechanisms, frequency of use, product, or consumer-based characteristics is unknown. These considerations notwithstanding, in a population of HDS users, the incidence of DILI is probably less than 1%.[28]

#

CLINICAL PRESENTATION OF HERBAL AND DIETARY SUPPLEMENT HEPATOTOXICITY

The clinical presentation of HDS-associated hepatotoxicity is, in effect, similar to that of DILI— the general patterns of presentation are either predominately hepatocellular or predominately cholestatic. In the former, elevations of serum ALT or aspartate aminotransferase (AST) levels predominate and reflect direct hepatocyte injury with less prominent elevation of alkaline phosphatase (AP). This is in contrast to the cholestatic presentation, in which elevation in the AP, often with an accompanying rise in total serum bilirubin, predominates. This pattern reflects impairment of bile flow due to direct injury to the bile secretory apparatus. Certain HDS produce a biochemical picture of liver injury that is highly characteristic and thus useful in assigning attribution. A more complete discussion of the clinical presentation of DILI can be found elsewhere in this issue of the Seminars in Liver Disease and through other recent reviews.[30] [31] [32]

Although not a complete compendium, the information presented in the sections that follow is intended to provide familiarity with various commonly used HDS that have been associated with hepatotoxicity. Since last presented in the this journal,[33] new products causing liver injury have captured the public's attention. Other excellent reviews have described hepatotoxicity associated with HDS in greater detail.[34] [35] Table [3] provides a more complete list of selected HDS that have been linked to hepatotoxicity.

Table 3 Selected Herbal and Dietary Supplements Linked to Hepatotoxicity
Product
Androstenedione
Atractylis gummifera
Black cohosh
Callilepis laureola
Chaparral
Chinese herbal medicines (certain constituents)
Germander
Greater celandine
Green tea extract
Herbalife (not all products)
Hydroxycut® (not all products)
Kava
Licorice
LipoKinetix
Mistletoe
Pennyroyal
Pyrrolizidine alkaloids
Senna
Usnic acid
Valerian
#

Hydroxycut

On May 1, 2009, the FDA posted a warning on Hydroxycut products (Iovate Health Sciences Inc., Oakville, Ontario, Canada) advising consumers to stop using several products with this brand name due to concerns of hepatotoxicity.[36] The FDA received 23 reports of liver injury ranging from jaundice to liver failure leading to requiring liver transplant surgery. In total, 14 Hydroxycut products were recalled by the manufacturer as a result of this FDA action.

Many different products were marketed under the Hydroxycut name, and most consist of a blend of substances. The Hydroxycut products were marketed for various purposes, including weight management and body building. Initial reports of hepatotoxicity attributed to Hydroxycut appeared in the literature in 2005.[37] Since that time, there have been others.[38] [39] [40] Too little has been published to establish a common clinical pattern of presentation, but many cases appear to have liver injury onset after several weeks of daily exposure. Patients present, variably, with cholestatic or hepatocellular injury patterns.

#

Herbalife

Herbalife products (Herbalife International of America, Inc., Los Angeles, CA) are marketed for various purposes including weight management, energy and fitness, and “targeted nutrition,” which addresses such problems as stress management and digestive health.[41] Several cases of hepatotoxicity have been attributed to Herbalife® products.[42] [43] [44] [45] Typically, the injury pattern is hepatocellular and jaundice is common. The latency period from product use to liver injury onset is highly variable, ranging from 2 months to several years. Several cases of ALF have been reported, and at least two patients required liver transplant surgery.[42] [43]

Products such as Herbalife make pinpointing the culprit hepatotoxin very difficult because each product may have many constituents. However, several aspects of hepatotoxicity attributable to Herbalife merit special attention. First, the reported cases arise in geographically distinct areas, raising the possibility of regional variation in product quality; of course, the geographical nature of the reports may also be the result of clinician initiative to report. Furthermore, a recent report implicated microbial contamination with Bacillus subtillis,[23] raising the concern that microbial contamination may play a role in hepatotoxicity.

#

Anabolic Steroid

Anabolic steroids were classified as class III controlled substances in 1991, and regulation of these substances was further expanded in 2004.[46] The spirit of this legislation was to limit access to anabolic steroids and their precursors, given the known adverse hepatic and systemic effects.[47] Nonetheless, anabolic steroids remain available, in some form, as dietary supplements. Awareness of this potential problem was raised by an article in the lay press in 2005,[48] and underscored by a 2007 report of associated hepatotoxicity.[49] Anabolic steroids have been recognized for decades as a cause of many forms of liver disease, including pure intrahepatic cholestasis and peliosis hepatis, as well as space-occupying lesions, including adenoma and hepatocellular carcinoma.[50] [51]

It is a sobering exercise to browse the Internet and find the ease of access to anabolic steroids and their precursors. And it is even more alarming that 2.2% of 12th-grade students reported having used anabolic steroids in a 2007 survey.[52] Thus, despite legislation, hepatotoxicity due to anabolic steroids or its precursors will likely continue to be seen.

#

Green Tea

Green tea extract is a frequent ingredient in many HDS. It is obtained from the leaves of Camellia sinensis and commonly found in HDS used predominantly for weight loss. The most prominent regulatory action against green tea-containing products related to Exolise, which was withdrawn from Spain and France in 2003.[53] It was postulated that the hydroalcoholic extract in this product was the cause of liver injury in 13 patients,[54] although this has not been confirmed. Hepatotoxicity has also been seen with green tea leaf extract.[55]

Mazzanti et al reviewed the published literature on green tea hepatotoxicity.[56] Injury usually develops within 3 months from commencement of use. The majority of cases present with an acute hepatocellular injury pattern, and most recover with cessation of use.[56] [57] In a systematic review of the available literature by the USP, it was concluded that there is reason to be concerned that extracts of green tea may predispose to hepatotoxicity, although a warning on the label has not been required.[58] Nonetheless, this review underscores the concerns previously raised over green tea-containing products.[59] [60]

Several lines of preclinical and human data point to the green tea catechin as the culprit of hepatotoxicity.[61] [62] [63] Further, toxicity may be potentiated by consuming green tea extracts in a fasted state.[61] [64] [65] The exact mechanism of injury, or conditions leading to it, are not fully understood but worthy of additional investigation.

#

Black Cohosh

Black cohosh products, derived from the plant Cimicifuga racemosa and native to North America, have been used to treat menopausal symptoms, joint pain, myalgia, bronchitis, and obesity.[34] The literature contains several reports of attributable hepatotoxicity, and additional reports are summarized elsewhere.[66] [67] [68] [69] [70] [71] Clinical presentation varies from an autoimmune-like hepatitis to ALF.

In its systematic review of black cohosh case reports of hepatotoxicity, the USP determined that the evidence was sufficient to include a label cautionary statement for the USP monograph. However, based on application of causality assessment of the Council for International Organizations of Medical Sciences to the most suspicious four of 42 cases reported to the European Medicines Agency, Teschke and Schwarzenboeck challenged the association of hepatotoxicity with black cohosh.[72]

#

Usnic Acid

Usnic acid is extracted from lichens, fungi, and algae and is recognized for its biological effects, which have been reviewed elsewhere.[73] Its purported mechanism of action and toxicity stems from its action as a membrane uncoupler.[73] In vitro toxicological studies with rat and mouse hepatocytes showed that exposure to usnic acid induced release of hepatic enzymes, reduction in glutathione content, damage to cell membranes, and necrosis.[74] [75] Uncoupling of the respiratory chain with resultant oxidative stress was demonstrated.[74] In vivo toxicity data indicate that skeletal muscle toxicity may also occur.[73]

The value of membrane uncoupling agents in weight loss has been known for decades, following experience with the 2,4-dintrophenols, which have a similar mechanism of action to usnic acid.[73] [76] However, the multiorgan toxicity of 2,4-dintrophenol became apparent when the product was linked to severe disease and death,[77] and it was removed from the market. Several cases of human hepatotoxicity have been seen with usnic acid-containing compounds.[78] [79] The clinical picture described in most cases is predominantly severe hepatocellular injury. Disease onset usually occurs with a latency period of less than 3 months.

The most prominent regulatory action concerning usnic acid-containing products concerned LipoKinetix. Several cases were associated with ALF, and some resulted in the need for liver transplant surgery.[26] [80] [81] LipoKinetix was removed from the market in 2001.

#

Pyrrolizidine Alkaloids

Known for several years to be capable of inducing veno-occlusive disease, pyrrolizidine alkaloids are the active ingredient of several herbal preparations, including comfrey tea.[82] [83] [84] They are derived from several plant species, including Symphytum officinale, from which comfrey tea is made, and Senecio. However, pyrrolizidine alkaloids are found in more than 350 plant species worldwide.[35] Cases of hepatotoxicity have been described from the Southeastern United States and from around the world following ingestion of products from various species of pyrrolizidine alkaloid-producing plants.[83] [85] [86] [87] [88] [89]

As a syndrome of hepatotoxicity, patients typically present with hepatomegaly and ascites, reflecting sinusoidal obstruction. There may be varying levels of acuity, but rapid progression to death is not uncommon. A small proportion of patients may progress to a protracted course leading to cirrhosis and the manifestations of portal hypertension. These possibilities notwithstanding, recovery has been described.[33] [85] [89] [90] [91] [92] Because of the injury attributable to pyrrolizidine alkaloids, the FDA recommended removal of comfrey products from the market in 2001.[93]

#

Chaparral

Chaparral is derived from the creosote bush, native to the southwestern United States and Mexico. It has been used for numerous ailments by Native Americans, including rheumatological complaints and obesity. The most compelling line of evidence linking chaparral to hepatotoxicity results from a series of case reports describing liver disease ranging from acute hepatocellular injury to cholestatic jaundice.[94] [95] [96] [97] [98]

#

Traditional Chinese Herbal Medicines

Blends of herbs rendered by Chinese medicine practitioners are difficult to characterize. This makes the task of assigning causality to any one ingredient, or interplay among ingredients, nearly impossible. Nonetheless, cases of severe hepatitis and liver failure due to using these products have been reported.[99] [100]

#

DIAGNOSIS OF HERBAL AND DIETARY SUPPLEMENT HEPATOTOXICITY

Causality assessment is the process whereby liver disease can be attributed to a drug or HDS on a semiquantitative scale with varying degrees of certainty. Generally speaking, there are several key elements to causality assessment, including the following: (1) a drug or HDS must be suspected as the cause of injury based on its use preceding the onset of injury, (2) other more common causes of injury must be excluded, and (3) one must assess the response of the injury upon removal or reintroduction of the drug. Two instruments are available to assess causality, and they have both been applied to cases of HDS-associated hepatotoxicity.[67] [72] [101] [102] [103] [104] Causality assessment in DILI is an area of active scholarly interest and has been evaluated by others.[105]

Several important aspects of HDS-induced hepatotoxicity confound the process of causality assessment. First, it is not unusual for patients to use HDS continuously or intermittently over protracted periods of time. Current causality assessment methods assign a lower score, and thus a lower likelihood of attribution, to a longer latency period. In addition, the number of products available and marketed under various brands, the complexity and multiplicity of ingredients, and the frequent simultaneous use of multiple HDS products further confound accurate attribution. That is, one can make a diagnosis of HDS hepatotoxicity with a high degree of confidence; however, it may be impossible to identify which specific ingredient is responsible. Furthermore, one cannot exclude the possibility of product adulteration or of a drug-HDS interaction as the culprit for toxicity.

#

PREVENTION

A necessary step to minimize the risk of HDS products to consumers is to provide accurate and complete product information. However, this information is frequently absent on Internet Web sites.[106] A multidimensional strategy for better consumer and healthcare provider education, and more complete adverse event reporting, as discussed by Gardiner et al,[107] are likely to have a significant impact on identifying unsafe products. The facts that many patients do not disclose use of HDS[1] [5] [108] and that healthcare providers have an inadequate understanding of HDS[109] [110] underscore the need for such an approach.

The value of spontaneous reporting and published reports to identify potentially dangerous HDS is evident through the recent FDA warning concerning Hydroxycut. Providers and patients must continue to report suspected HDS-associated liver injury through the MedWatch mechanism.[111] Unfortunately, it is estimated that less than 1% of adverse reactions to dietary supplements are reported.[112]

Arguably, the greatest preventative measure against HDS-associated hepatotoxicity will come through increased regulation. Large gaps in manufacturing, distribution, and marketing regulation need to be closed. For example, although products like Hydroxycut may be recalled, under the current U.S. law, similar products may be introduced by a different manufacturer without prior approval from the FDA.

The current USP standards should not be confused with medical recommendations to providers; rather, the USP conducts safety reviews for HDS to provide appropriate advice through its monographs and publications. Providers and consumers can use these sources to identify dietary ingredients for which safety concerns exist. But because HDS are generally consumed without professional supervision or monitoring, products that contain these ingredients should be used with caution by patients. Their use should be disclosed to providers who, in turn, can inform patients of the signs of possible toxicity. Finally, our understanding of the effect of host factors, HDS dose, duration, and HDS-drug interactions, and product adulteration in the development of hepatotoxicity is in its infancy. The DILIN prospective study and other studies will endeavor to explore many of these issues in the years to come.

#

CONCLUSION

Hepatotoxicity due to HDS is an under-reported, yet not uncommon phenomenon due to their ubiquitous presence and widespread use. The regulatory framework to govern HDS safety and quality needs to be strengthened. Improved conformity with USP standards will hopefully provide transparency of product quality and contents. The combined effect of more uniform regulatory conformity by manufacturers; more frequent adverse event reporting by patients and providers; and ongoing prospective research, such as that being conducted by DILIN, can lead to a safer environment for HDS use by consumers.

#

ACKNOWLEDGMENTS

The author wishes to thank Maricruz Vega, M.PH., for her editorial assistance in preparation of the manuscript, and Dandapantula N. Sarma, Ph.D., R.Ph. of the United States Pharmacopeia, for his critical review.

#

ABBREVIATIONS

  • ALF acute liver failure

  • ALT alanine aminotransferase

  • AP alkaline phosphatase

  • AST aspartate aminotransferase

  • DILI drug-induced liver injury

  • DILIN Drug-Induced Liver Injury Network

  • DSHEA Dietary Supplement Health and Education Act

  • FDA U.S. Food and Drug Administration

  • FD&C U.S. Federal Food, Drug, and Cosmetic Act

  • cGMP current Good Manufacturing Practice

  • HDS herbal and dietary supplement(s)

  • USP United States Pharmacopeia

#

REFERENCES

Victor J NavarroM.D. 

Professor of Medicine, Pharmacology and Experimental Therapeutics, Division of Gastroenterology and Hepatology, Thomas Jefferson University

132 S. 10th Street, Suite 480 Main Building, Philadelphia, PA 19107

Email: victor.navarro@jefferson.edu

#

REFERENCES

Victor J NavarroM.D. 

Professor of Medicine, Pharmacology and Experimental Therapeutics, Division of Gastroenterology and Hepatology, Thomas Jefferson University

132 S. 10th Street, Suite 480 Main Building, Philadelphia, PA 19107

Email: victor.navarro@jefferson.edu

   Permissions and Reprints