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Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
Hepatotoxicidad de productos naturales y suplementos dietéticos
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Hepatotoxicidad de productos naturales y suplementos dietéticos

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(Hepatotoxicidad de productos naturales y suplementos dietéticos) Hepatotoxicity of Herbalsand Dietary Supplements

(Hepatotoxicidad de productos naturales y suplementos dietéticos) Hepatotoxicity of Herbalsand Dietary Supplements

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  • 1. C H A P T E R35Hepatotoxicity of Herbals andDietary SupplementsLeonard Seeff1, Felix Stickel2, and Victor J. Navarro31The Hill Group, Bethesda, and US Food and Drug Administration, Silver Spring, Maryland, USA, 2University ofBerne, Bern, Switzerland, 3Thomas Jefferson University, Philadelphia, Pennsylvania, USAO U T L I N EIntroduction 632Epidemiology of and Expenditure on Herbals andDietary Supplements 632Prevalence of Complementary and AlternativeMedicine Use in the United States 632Prevalence of Complementary and AlternativeMedicine Use in Other Parts of the World 633Complementary and Alternative Medicine Use forChronic Illnesses 633Expenditure on Complementary and AlternativeMedicine Use 633Origin and Production of Herbals and Botanicalsfor Medicinal Purposes 633Regulation of Dietary Supplements 634The United States 634Other Regions 635European Union 635United Kingdom 635Canada 635Global Regulatory Environment for HerbalMedicinal Products 635The Use of Herbal Products to Treat LiverDisease 636Philosophy 636Herbals to Treat Viral Hepatitis 636Silymarin (Milk Thistle) 637Glycyrrhizin 637Sho-Saiko-To (TJ-9) 638Traditional Chinese Medicine 638Phyllanthus amarus 638Liver Injury Caused by Herbals and DietarySupplements 639Causality Assessment for Hepatotoxicity Due toHerbals and Dietary Supplements 639Limitations of Causality Assessment for HepatotoxicityDue to Herbals and Dietary Supplements 639Herbal Products Associated with Liver Injury 640Herbals Containing Pyrrolizidine Alkaloids 641Chinese Herbs 641Germander 644Chaparral 644Atractylis gummifera and Callilepis laureola 645Pennyroyal 645Greater Celandine 645Kava 645Black Cohosh (Cimicifuga racemosa) 646Miscellaneous 646Dietary Supplements Associated with Liver Injury 647Green Tea (Camellia Sinensis) 647Herbalife 647Usnic Acid 648Hydroxycut 648Natural Toxins 648Aflatoxins 648Ackee Fruit 649Bacillus cereus 649Microcystins 649Conclusions 650References 650631Drug-Induced Liver Disease.DOI: http://dx.doi.org/10.1016/B978-0-12-387817-5.00035-2 © 2013 Elsevier Inc. All rights reserved.
  • 2. INTRODUCTIONCenturies before globalization and the ability totravel widely, indigenous peoples relied for treatmentof diseases on what is now referred to as alternativemedicine. This included among others, prayer, animalsacrifice, incantations, scarifications, massage, bodymanipulations, acupressure, acupuncture, and moxi-bustion (burning mugwort near an acupuncture site).In addition, virtually all peoples of the world utilizedproducts derived from plants and trees for medicinalpurposes, a practice dating back centuries, especiallyin the Far East. Herbals used for treatment were, andcontinue to be, extracted from the seeds, roots, stems,leaves, berries, barks, and flowers of plants and trees,which vary by region, depending on the local weather,geographic location, geographic elevation, and otherconditions [1].Westernized, pharmaceutically developed medica-tions began to be introduced only a little more than acentury ago and, indeed, some drugs, such as digitalis,ephedrine, ipecac, quinine, salicylic acid, and others,including more recently, vincristine and camptothecin,are actually derived from plants. Over the ensuingcentury, there has been an explosive increase in thenumbers and types of commercial drugs developedthrough chemical and molecular biologic manipula-tion and synthesis that are evaluated in well-controlled trials to determine their effectiveness andsafety, thus clearly revolutionizing medical care.Patients have obviously welcomed and benefittedfrom these new medicinal discoveries, but some haveexpressed concern about the often high cost and thefact that a number of drugs are associated withuncomfortable and sometimes serious side effects.For these reasons, and because many consumersfeel that general medical care has become too complex,time restricted, and seemingly less receptive, somehave elected to assume greater personal care of theirhealth by turning to the use of complementary andalternative medicine (CAM), which includes the use ofherbals and dietary supplements (HDS); their belief isthat herbals, having been used for centuries, must beeffective and safe. Some will use only herbals for theirmedical care, referred to as alternative medicine, whileothers will take them together with commercial drugs,referred to as complementary medicine, hence the termCAM. A recent review of the published data aimed atdetermining expectations among proponents of CAMuse found that the goals of users, in order of preva-lence, are to influence the natural history of their dis-ease, promote well-being, reduce side effects, takecontrol of one’s health, relieve symptoms, boost theimmune system, provide emotional support, improvetheir quality of life, cope better with illness, supportnatural healing, and others [2].EPIDEMIOLOGY OF AND EXPENDITUREON HERBALS AND DIETARYSUPPLEMENTSPrevalence of Complementary and AlternativeMedicine Use in the United StatesNumerous surveys have been undertaken in theUnited States and elsewhere to determine the preva-lence of use of HDS in the general public and amongthose with various medical conditions. A telephone sur-vey performed in the United States in 1990 revealedthat 34% of the general population was currently utiliz-ing CAM [3], with 2.5% using herbal medicines, andthat 67.6% had used at least one CAM therapy duringtheir lifetime [4]. A follow-up survey in 1997 by thesame investigators found that the frequency of CAMuse had increased to 42%, with 12.1% now admittingto use of herbals [5]. Information has also comefrom reviews of the National Health and NutritionExamination Survey (NHANES) databases. In theNHANES I study, covering the period 1971À1974, 23%of respondents reported using vitamin supplements [6].In the NHANES II survey of 1976À1980, the figure forusers of supplements was 35% [7]. The figure in theNHANES III survey (1988À1994) rose to 30À42% formen and 42À55% for women [8], while for NHANES IV,covering 1999À2000, the overall figure was 52% [9].Another source of information in the United States isdata from the National Health Interview Survey (NHIS),which covers the noninstitutionalized US civilian popu-lation. In this survey of 1999, 28.9% of adults admitted tousing at least one CAM therapy in the preceding year,with 9.6% representing herbal medicines [10]. A resur-vey of this database 3 years later revealed that 19% ofparticipants had used herbs or supplements in the previ-ous year, from which it was estimated that 38.2 millionUS adults had taken herbals or supplements during2002, with their use being significantly higher in womenthan men [11]. A far higher frequency of dietary supple-ment use in the same year (2002) was found in a Healthand Dietary Survey sponsored by the US Food and DrugAdministration (FDA): 73% of the noninstitutionalizedUS adult population admitted the use of dietary supple-ments in the preceding 12 months, with approximatelyhalf using herbs or botanicals [12]. Despite variations inthe reported rates of HDS use, the data collectively indi-cate that their use has been increasing in the UnitedStates over time. This is noteworthy, since in virtually allsurveys, patients are reluctant to inform their health care632 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 3. providers of their use of CAM therapies unless specifi-cally asked and, even then, somewhat grudgingly.Hence, for reasons to be discussed, it is essential formedical providers to consistently and nondisparaginglyinquire whether their patients are presently or have inthe past used herbal products, what the products are,and where they were acquired.Prevalence of Complementary and AlternativeMedicine Use in Other Parts of the WorldCAM use is, of course, practiced worldwide, and insome countries represents the primary form of medici-nal care. General surveys from Europe attest to thehigh frequency of herbal use in that continent [13,14],including reports from such countries as Germany[15], Italy [16], Sweden [17], and Spain [18]. Highusage is also reported from the Middle East, includingJordan [19], the United Arab Emirates [20], Turkey[21], and Israel [22]. Not surprising is the high fre-quency of use in the Far East [23À26] and Africa[27À30]; a high frequency has also been reported inAustralia [31]. Fact sheets from the World HealthOrganization (WHO) indicate that in some Asian andAfrican countries, 80% of the population depend ontraditional medicine for their primary health care [32].Complementary and Alternative Medicine Usefor Chronic IllnessesA large body of published data also attests to thefrequent use of CAM, including herbals, amongpersons with a variety of chronic diseases [33]. Thisincludes, but is not limited to, those with humanimmunodeficiency virus (HIV)/acquired immunodefi-ciency syndrome [27,34], rheumatologic disease [35],cancers [29,36], chronic pain [37], cardiovasculardisease [38], diabetes [39], and liver diseases [40À46].Regarding liver disease, 23% of enrollees in a long-term treatment trial of persons with chronic hepatitisC admitted to their current use (an additional 21%having used them in the past), despite havingpreviously suffered uncomfortable antiviral treatmentand now committing themselves to another 3.5 yearsof treatment with pegylated interferon [42].Expenditure on Complementary and AlternativeMedicine UseThe financial outlay on CAM therapies in theUnited States, mostly out-of-pocket expenses, is vast.An analysis conducted in 1997 conservatively esti-mated that expenditure on CAM therapies was US$27billion, taking into account the cost of both purchasingherbal products and vitamin and CAM professionalservices [5]. This amount was said to be comparable tothe total out-of-pocket expenditures for all physicianservices. The estimated expenditure 7 years earlier hadbeen US$14.6 billion. In 2007, the estimate had risen toUS$33.9 billion in the United States, based on analysesperformed at the National Center for Complementaryand Alternative Medicine (NCCAM) and the NationalInstitutes of Health (NIH), using data derived from theNHIS [47]. Placing these data in context, the research-ers noted that the cost to purchase natural productswas “equivalent to about 1/3 of total out-of-pocketspending on prescription drugs,” and that the cost for“CAM practitioner visits was equivalent to approxi-mately 1/4 of total out-of-pocket spending on physi-cian visits.” In their estimate, in 2007 38% of adultsand 12% of children in the United States had utilizedsome form of CAM [47]. More recently, data publishedby the American Botanical Council showed that duringthe period 1999À2009 there had been an estimatedincrease in sales and monetary outlay for herbals inthe United States every year in that decade, except for2002 and 2003 (Table 35-1) [48].ORIGIN AND PRODUCTION OFHERBALS AND BOTANICALS FORMEDICINAL PURPOSESThe use of botanicals as medicines dates backthousands of years in many cultures, particularly inFar Eastern countries, such as China. However, herbsTABLE 35-1 Total Estimated Herb Sales in the United States,1999À2009Year US$ Total Sales (Billions) % Change1999 4.110 1 2.72000 4.230 1 2.92001 4.356 1 3.02002 4.278 2 2.72003 4.146 2 2.22004 4.290 1 3.52005 4.381 1 2.12006 4.561 1 4.12007 4.759 1 4.32008 4.800 1 0.92009 5.030 1 4.82010 5.200 1 3.3633ORIGIN AND PRODUCTION OF HERBALS AND BOTANICALS FOR MEDICINAL PURPOSESIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 4. for healing purposes have also been used in the distantpast by Greeks, Egyptians, Indians, and indigenouspeoples from Africa and the South Sea Islands and byNative Americans. Unlike Western medicines that aregenerally designed to treat a specific disease or set ofsymptoms, the traditional use of herbals is meant tohave a broad impact on strengthening the body’s abil-ity to deal with a variety of illnesses. Thus, herbalismis an art rather than a science. Herbals in the tradi-tional Chinese medicine (TCM) culture have consistedof single products believed, through trial and error, toinduce a particular response for a given set of symp-toms, but may be mixed or bundled with other specificherbs that together are considered complementary andtherefore more effective. The intent is to readjust andbring into balance the yin and yang, i.e., the polaropposites, that are possibly responsible for healthproblems. This requires the expertise of an experiencedtraditional herbalist who selects the most effectiveherb, which may differ according to the season ofharvest, soil characteristics, prevailing climate, andelevation where grown. Many such herbalists disputethe current pharmacological effort to chemicallyisolate and extract the presumed active ingredientbecause the plant is believed to contain other sub-stances that may enhance the healing process and alsoprotect against possible toxicity.In addition to the traditional use of herbals, consist-ing either of a single ingredient or a carefully selectedbut restricted mixture of ingredients, there has been adramatic increase in the use of commercially devel-oped products that often contain multiple ingredients,as many as a dozen or more. These may be groupedtogether not necessarily because they are known tocomplement one another, but because each individualingredient is reputed to have an independently posi-tive effect. They are advertised as being useful forhealthy living, bodybuilding, weight loss, weight gain,or an improved sense of well-being. Many are sold inhealth food stores, but some are advertised on theInternet, sometimes by fly-by-night companies or indi-viduals [49].The nature of herbal production unfortunately lendsitself to contamination with potentially toxic items orto the unexpected addition of adulterants. The originalherb may have been specifically cultivated, requiringspraying with pesticides, or collected from the wild.After it is grown, it is harvested, dried naturally orartificially, cleansed and sorted, and then subjected toextraction of constituents using organic solvents,maceration, percolation, countercurrent extraction,extraction with supercritical gases, irradiation, orcold compression. Extracts are then usually storedand packaged prior to distribution. At any step, theremay be contamination with microbials [50,51],mycotoxins [52], and heavy metals [49,53À58], orthere may be adulteration with pharmaceuticals [59],which have included chlordiazepoxide, chlormethia-zole, chlorpheniramine, diclofenac, diphenhydramine,hydrochlorothiazide, promethazine, sildenafil citrate,and triamterene [60], as well as benzodiazepines,corticosteroids, and antiinflammatory drugs [61].Specific examples are an herbal product, PC-SPES,used to treat prostate cancer, that has been found tocontain pharmacological dosages of diethylstilbestrol[62], indomethacin [63], and warfarin [63,64] andherbal products marketed to treat erectile dysfunction,found to be contaminated with phosphodiesterase type5 inhibitors [65]. A disturbing finding from theNHANES data obtained between 1999 and 2004 wasthat blood levels of lead were significantly higherin women who used herbal supplements thanamong nonusers, the relative difference being 10À24%higher [66].REGULATION OF DIETARYSUPPLEMENTSThe United StatesPreceded by a vigorous and sometimes rancorousdebate among stakeholders, the US Congress promul-gated the Dietary Supplement and Education Act of1994 (DSHEA), signed into law on 15 October 1994,during the waning moments of the 103rd Congress.Prior to that time, the FDA permitted manufacturers ofdrugs but not conventional food and dietary supple-ments to label their products with claims of diseaseprevention, mitigation, treatment, or cure. The Act wastherefore viewed by the supplement industry as apositive step, since the FDA would now regulate die-tary supplements and its ingredients differently fromthose regulating conventional foods and drugs. Themanufacturers of dietary supplements would them-selves become responsible for ensuring that supple-ments and their ingredients were safe before itsmarketing. Furthermore, manufacturers would notneed to register their product with the FDA or getFDA approval before producing or selling theirsupplements. Manufacturers did have to ensure thattheir product labeling information was truthful andnot misleading and that it complied with current goodmanufacturing practices (cGMP) for quality control.The role left to the FDA was to take action against anyunsafe dietary supplement product, but only once itreached the market. Accordingly, the manufacturer,packager, or distributor of dietary supplementsmarketed in the United States would be required tonotify the FDA of all adverse events associated634 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 5. with the use of the dietary supplement. Unfortunately,it is estimated that less than 1% of instances ofadverse events caused by herbals and dietary supple-ments are in fact reported to the FDA (InspectorGeneral, Department of Health and HumanServices; Government Accountability Office Report toCongressional Requesters, January 2009, DietarySupplements: FDA Should Take Further Actions toImprove Oversight and Consumer Understanding). Inthis regard, in a survey published in 2001 [67], while alarge proportion of interviewed persons admittedusing supplements, most did not inform their regularphysicians of this use because they believed that theirphysicians knew little about these products or werebiased against their use, and many were convinced oftheir value and would continue to use them even ifscientifically conducted studies did not prove theireffectiveness. However, the majority believed that theFDA should be permitted to review the safety of theseproducts prior to their distribution and, if foundunsafe, that they should be removed from use, andfurthermore that government regulation should beincreased to ensure that claims of safety were in facttrue. In 2007, the FDA required a modification to thecGMPs regarding manufacturing, packaging, labeling,and holding operations for dietary supplements and aFinal Rule was published on 22 June 2007. Morerecently, the FDA has developed draft guidance forindustry regarding new dietary ingredients notifica-tion. Needless to say, there continues to be controversyabout the Act, including the question of what actuallyconstitutes a dietary supplement and what representsa new dietary ingredient [68].Other RegionsOther regions that have had or have begun todevelop regulations regarding herbals include theEuropean Union, the United Kingdom, and Canada.European UnionCurrent regulations are based on the TraditionalHerbals Medicine Products Directive 2004/24/ECannounced on 31 March 2004 [69]. The intent wasthat all traditional medicines in health food shops andpharmacies must be formally registered and theproducts approved before they could be sold.Acceptable products for licensure were considered tobe those whose use was “plausible on the basis oflong-standing use and experience” and whose qualityand safety could be guaranteed. The duration requiredto prove their safety was at least 30 years in all, and atleast 15 years in the EU. The Directive allowed the pas-sage of 7 years from its announcement formanufacturers to gather the necessary information ontheir products and on 1 May 2011, the requirementthat herbal medicines and their ingredients be regis-tered with evidence of safety went into effect [69].Based on this Directive, no herbals from China wouldmeet the specifications and they are therefore currentlybanned in the EU.United KingdomThe Herbal Medicines Advisory Committee wasestablished in 2005 to advise on the safety, quality, andefficacy of herbal medicinal products for human use.Although there is no requirement for proof of efficacy,pharmacological effects must be plausible andsupported by long-standing use and experience. Theherbal medicinal product must be eligible under theTraditional Herbals Medicine Products Directive 2004/24/EC [70]. Prior to this, regulation of the herbalindustry was covered by the 1968 Medicines Act.Under the current act, suspected adverse reactions toherbal medicines are reported voluntarily, but arecompulsory for manufacturers with registration of aproduct under the Traditional Herbal MedicinesRegistration Scheme that has published guidelines forretailers, wholesalers, importers, and manufacturers onits requirements [71].CanadaConsultations with various stakeholders led to thecreation of the Natural Health Products Regulationthat addresses the availability and safety of naturalhealth products. All natural health products must havea product license and manufacturers, packagers,labelers, and importers must have site licenses.Licensing requires specific labeling and packagingrequirements, cGMP, and evidence of safety andefficacy.Global Regulatory Environment for HerbalMedicinal ProductsThe WHO, in response to the proliferation of herbalmedicine use in many countries, both developed andunderdeveloped, as well as the safety concernssurrounding herbal medicines raised by its membercountries, conducted a survey of the 191 memberstates in 2001 that explored policies, regulations, andareas for more action in the arena of traditionaland complementary and alternative medications(TM/CAM). Among 141 respondents, only 45 (32%)reported having a policy on TM/CAM; these policiesare loosely defined and include laws, regulations, andconsideration of intellectual property issues. Regardingregulations for herbal medicines, 53 (37%) respondentsreported having laws and regulations in place as of2003, although the majority (86 of the 141 respondents;635REGULATION OF DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 6. 61%) had a registration system in place for herbalmedicines. Responding member states requestedcontinued support from the WHO to address the lackof research, appropriate control mechanisms, andformalized education and training in the use ofTM/CAM [72].THE USE OF HERBAL PRODUCTS TOTREAT LIVER DISEASEPhilosophyThere are vast differences in the views of Westernand Eastern practitioners regarding the philosophy ofhealth care administration. The Western approach totreatment consists largely of the administration ofdrugs or the performance of surgery targeting aspecific condition or disease. It requires defining theetiology and pathogenesis of the disease, developingand utilizing medications directed specifically at theillness, and conducting rigorous, scientifically definedstudies to establish the efficacy and safety of medica-tions; thus, treatment directed at the disease isevidence based. In contrast, the Eastern approaches areintegrative and holistic, directed at the body and mindrather than the disease, and based on the view that inorder to preserve health, the vital energy that main-tains life must flow freely through the entire body [73].Ideally, with regard to the use of herbals, treatment isadministered by an experienced local healer whoseknowledge derives from information passed fromgeneration to generation.In the West, people tend to use herbals or dietarysupplements largely to maintain or improve their well-being or health, for bodybuilding purposes, or to treatchronic rather than acute illness; the focus on chronicdiseases is because few conventional medicationsactually cure chronic diseases and many are associatedwith uncomfortable or even serious adverse effects.Moreover, cost issues can represent a burden fordeveloping countries. The focus on herbals comesfrom the belief that, having been used for centuries,they are likely to be effective but, more importantly,that being natural they must surely be safe. Westernpractitioners, however, tend to decry this alternativeapproach, particularly the use of herbals, because oftheir seeming unscientific origins, the lack of well-controlled trials to prove their efficacy and safety, theconcern of contamination and adulteration, and thenot uncommon proclamation of a miracle cure, oftendelivered as a testimonial. Unsurprisingly, therefore,herbal users tend not to inform their conventionalhealth care practitioners of this fact for fear of beingdisparaged or reprimanded. However, in view of theprolific use of herbals, because they are sometimesused as a substitute for potentially curative conven-tional medication by persons with serious disease, andbecause many have been associated with severe, life-threatening side effects, it is essential that conventionalhealth care practitioners educate themselves about thisform of health care and be willing to consideratelyquestion their patients about its utilization or advisethem on how to use herbals safely.While HDS are most often employed in Westerncountries to improve or sustain well-being and generalhealth, for weight reduction, and for muscle-buildingpurposes by bodybuilders, the present discussion willbe confined to their recent use for the treatment ofliver diseases, predominantly viral hepatitis.Herbals to Treat Viral HepatitisFollowing the discoveries of the hepatitis A, B, andC viruses (HAV, HBV, and HCV), pharmaceuticalcompanies attempted to identify and evaluate medica-tions in well-designed, controlled trials aimed largelyat treating patients with chronic hepatitis B and C.A number of drugs developed clearly representedvitally important advances in the management of thesechronic liver diseases but were initially found to beeffective in only a limited number of patients, wereassociated with frequent serious side effects, and theircosts were extremely high and, hence, could not beafforded by many affected individuals. Accordingly,viral hepatitis became and continues to be a primetarget for self-treatment with herbals.Various herbal products have been evaluated fortreating viral hepatitis, the most prominent beingsilymarin, glycyrrhizin, Japanese traditional medicine(Kampo medicine; TJ-9, Sho-Saiko-To), TCM, andPhyllanthus amarus [43,74]. Unfortunately, theadherence to generally accepted scientific methods toevaluate drug therapy has been rare; few studies havebeen conducted as randomized, blinded, controlledtrials or have estimated sample size or defined endpoints ahead of time, have ensured a homogeneouspopulation or disease characteristics, or have measuredoutcome using appropriate serological tests or otherbiomarkers, let alone establishing hard end points suchas histology or sustained viral clearance. Moreover,there is uncertainty about the quality of the herbalsevaluated in studies, whether or not they are appropri-ately absorbed, and the adequacy of doses given.Finally, reporting of results has lacked uniformity andis often biased by the reporting of only positive results.In this regard, a group of investigators collaborated inthe 1990s to develop standards for reporting results ofrandomized controlled trials, termed the Consolidated636 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 7. Standards of Reporting Trials (or CONSORT) Statement[75]. Although this effort focused on reporting conven-tional drug results, it did include creating a modifiedversion for evaluating herbal medication [76,77].Silymarin (Milk Thistle)Silybum marianum has been used for centuries totreat liver and biliary disorders; in Europe, its use hasfocused on treating mushroom (Amanita phalloides)poisoning [78]. It is also the most common herbalproduct used by patients with chronic viral hepatitis[40À42]. Its main constituent is silymarin, consisting offour isomers: silibinin A and B, isosilibinin A and B,silichristin, and sildianin. Numerous studies indicatethat it has antioxidant, antifibrotic, and antiinflamma-tory activities, that it neutralizes free radicals andstabilizes cell membranes, and that it is cytoprotective[79À81]. Until recently, there has been no evidencethat it has antiviral properties.Two important early treatment trials brought atten-tion to silymarin as a potential therapy for chronicliver disease, focusing on alcoholic cirrhosis [82,83].The results of the two studies were, however,contradictory and data were compromised by highdropout rates and the lack of alcohol consumptionduring treatment. They were followed by a number ofother randomized, controlled trials involving patientswith alcoholic cirrhosis, acute and chronic viralhepatitis, and primary biliary cirrhosis, almost alladministering treatments for only 1À2 months’ dura-tion [43]. A Cochrane review of these trials concludedthat silymarin had no significant effect on reducingfibrosis, morbidity, or mortality, but noted that themethodological qualities of the trials were low [84].In 2007, a standardized silymarin extract (MK-001)was found for the first time to have antiviral activityagainst HCV [85]. In an in vitro study, standardizedsilymarin (MK-001) was shown to inhibit infection ofhuman hepatoma Huh7 and Huh7.5.1 cells by the JFH(Japanese fulminant hepatitis)-1 virus, expression oftumor necrosis factor (TNF-α) in anti-CD3-stimulatedperipheral blood mononuclear cells, and nuclearfactor NF-kappa-B (NFκB)-dependent transcription inHuh7 cells. Thus, silymarin appeared to exert anti-inflammatory and antiviral effects. A key study,published 1 year later, reported that silibinin givenintravenously dramatically reduced levels of HCVRNA in patients with chronic hepatitis C who had notresponded to previous standard treatment with pegy-lated interferon and ribavirin [86]. This unexpectedresult was noted in two protocols that involved admin-istering increasing doses of silibinin infused intrave-nously for 4 h for either 7 or 14 consecutive days,followed by pegylated interferon and ribavirin or bytriple therapy for up to 24 or 48 weeks. The inhibitoryeffect disappeared, however, when the silibinin infu-sion was completed. Other than mild gastrointestinalsymptoms, intravenous treatment with silymarin waswell tolerated. A similar antiviral inhibitory effect onHCV and on inhibition of HIV replication wasreported in patients coinfected with HIV plus HCV[87], and silymarin was also shown to prevent reinfec-tion with HCV of a liver graft following liver trans-plantation [88]. Additional studies to determine themechanistic effects of silymarin and silibinin on theHCV and on liver cell necrosis have continued to beperformed, yielding improved knowledge of the com-pound and suggesting that it may have a future role inthe treatment of patients with HCV infection [89À92].On this basis, the NCCAM and the National Instituteof Diabetes and Digestive and Kidney Disease, NIH,embarked on scientifically designed studies to evaluatesilymarin to treat patients with chronic hepatitis C whohad failed to respond to conventional pegylated inter-feron and ribavirin therapy, as well as for those withnonalcoholic steatohepatitis. Termed SyNCH, the studybegan as a phase I/II trial using a standardized milkthistle product (Legalon, Madaus AG, Frankfurt,Germany). The phase I study, designed to evaluateabsorption characteristics and pharmacokinetics, and todetermine effective doses, consisted of administeringincreasing oral doses of silymarin given at 8-h intervalsfor 7 days. Among its findings were that steady stateexposures suggested nonlinear pharmacokinetics, thatthe product appeared to be safe, and that it did not pro-duce a meaningful reduction in serum aminotransfer-ase levels or reduce serum levels of HCV RNA at lowerdoses, but that higher doses may overcome the low bio-availability [93]. Unfortunately, recently reportedresults of the hepatitis C trial indicate that treatmentwith oral doses of silymarin, even when pushed to thelimit of oral intake, did not lead to reduction of amino-transferase or HCV RNA levels [94]. Clearly, treatingby intravenous infusion, although seemingly effectivewhile the infusion continues, is not a viable treatmentoption. There may, however, be a role for silymarin asan adjunct to the new direct antiviral drugs that have orwill become available in the future, or even as an addi-tion to the older standard-of-care drugs, pegylatedinterferon and ribavirin, in parts of the world where thenew drugs are unavailable or cannot be afforded. Thesepossibilities will need to be investigated, however, infuture well-controlled trials [95].GlycyrrhizinDerived from the root of the licorice plant,Glycyrrhiza glabra, glycyrrhizin contains glycyrrheticacid, flavonoids, hydroxycoumarins, and β-sitosterol.It has been commonly used in Japan to treatchronic hepatitis, where it is referred to as Stronger637THE USE OF HERBAL PRODUCTS TO TREAT LIVER DISEASEIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 8. Neo-Minophagen C (SNMC); the parenteral prepara-tion contains 2% glycyrrhizin, 0.1% cysteine, and 2%glycine [96,97]. It appears to have antioxidant, anti-inflammatory, and immunosuppressive properties[98,99]. A number of clinical trials have used thisherbal to treat HCV infection, almost all consisting ofopen-label studies and involving short-term treatment,therefore most being of questionable quality [43]: someinvolved the treatment of hepatitis C, some the treat-ment of hepatitis B, and at least one was for the treat-ment of hepatocellular carcinoma (HCC) in chronichepatitis C. The main effect seen in these short-termstudies is an improvement in serum aminotransferaselevels without an effect on the HCV. Glycyrrhizin hasto be given intravenously (although liquid, powder,and tablet formulations have recently become availablebut have not yet been fully evaluated in persons withliver disease) and, because of its mineralocorticoidproperties, it can cause hypertension, fluid retention,and hypokalemia. Since only a few randomized con-trolled trials have been performed with this product,additional high quality trials are needed.Sho-Saiko-To (TJ-9)Used in Japan and China to treat chronic liver dis-eases, this is an herbal product containing sevenherbs (Bupleurum root, ginger rhizome, Ginseng root,Glycyrrhiza root, jujube fruit, Pinellia tuber, andScutellaria root) [100,101]. Its name, Sho-Saiko-To, isJapanese and TJ-9 is its label within the Kampo sys-tem of medicine, which comprises certain Chinesemedicinal herbal combinations adapted to Japanesepreference and categorized for composition, indica-tions for use, and presumed health effects. Withinthis system, another preparation, TJ-108, has an addi-tional apparent antiviral constituent, Gomisin A [102].Numerous experimental studies indicate that TJ-9 hasantifibrotic properties through downregulating RNAexpression of genes encoding procollagen alpha I andIII, inhibiting TIMP (metalloproteinase inhibitor),reducing expression of α-smooth muscle actin, lipidperoxidation in hepatocytes, and proliferation andactivation of hepatic stellate cells [103À106]. One ran-domized controlled trial and one pilot study with TJ-9 have been performed to treat patients with HBVinfection [107,108] and one randomized, controlledtrial was conducted to prevent HCC in patients withchronic HBV infection [109]. Each study suggestedsome positive effect without being convincingly wellperformed. A number of serious adverse effects havebeen reported with this product [110À113]. Clearly,additional well-designed trials are still necessary tofully determine whether this product has any mean-ingful effect on viral hepatitis.Traditional Chinese MedicineHerbals used in China date back centuries and theirmedicinal role differs from that required of therapyadministered in the modern-day Western world. Asalready noted, the philosophy behind this form oftreatment aims at stabilizing altered and opposingbody energies, i.e., to bring the yin and yang into align-ment. In TCM, several herbs are combined, one beingthe active King herb, while the others act synergisti-cally as its protective modifiers [114]. TCM may consistof half a dozen or even more herbs, including a prod-uct containing 10 herbs, referred to as compound 861,or 19 herbs, referred to as CH100, each of which con-tains the individual King herb [115À118]. Small studieswith these compounds have been performed to treatboth hepatitis B and C, and were reported to lead toreductions in serum enzymes but not the respectiveviruses; they have also been used to treat HCC andwere reported to have some efficacy, but in poorlyconducted studies [118]. Once again, better-designedstudies are needed to determine whether TCM has anyreal efficacy in treating chronic viral hepatitis.Phyllanthus amarusPlants of the Phyllanthus genus, found in tropicaland subtropical countries, contain alkaloids, flavo-noids, lignans, and terpenes. They have been used inIndia and China to treat diabetes, diarrhea, hepatitis B,and urinary tract conditions [119]. In vitro studiesusing human cell lines infected with the hepatitis Band woodchuck hepatitis viruses have found that theherbal has an inhibitory effect on HBV polymeraseactivity and that it decreases mRNA transcription inhepatitis B transgenic mice [120À122]. Several studieshave reported contradictory results using this herbal totreat patients with HBV infection: some reported lossof HBeAg and hepatitis B surface antigen (HBsAg),while others have failed to replicate these results. Thepositive effect, however, appeared more likely whenPhyllanthus was used together with interferon[123À126]. Thus, it appears that Phyllanthus may haveantiviral activity but, as is true for other herbal prod-ucts, there is a need for reliable controlled trials toprove that it is indeed an effective product.Numerous other herbal products have been studiedas treatments for liver disease, including Ayurvedicmedicines used in India (picrorrhiza and Liv-52),ellagic acid and curcumin, oxymatrine, and a widearray of Chinese herbal concoctions (Bing Gan Ling,Bing Gan Tang, Gansu, Qinggaan and Bushengranules, Yi Er Gan Tang, and Yi Zhu decoction)[43,127,128]. Valid evidence of efficacy for all theseproducts will remain uncertain until they are studiedusing appropriate scientific methods.638 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 9. LIVER INJURY CAUSED BY HERBALSAND DIETARY SUPPLEMENTSAlthough there is modestly encouraging but clearlyunproven or uncertain evidence for the efficacy of HDSfor the treatment of liver diseases—as has been hoped forby the public who use them—there is unquestioned evi-dence that they are sometimes responsible for causingliver injury, contrary to the belief of users. The realfrequency of hepatotoxicity from HDS is unknown.Furthermore, the types of products that cause hepatotox-icity in the United States and their relative frequencieshave been described only recently by the NIH-supportedDrug-Induced Liver Injury Network (DILIN) study. In apreliminary review of data collected from 93 patientswith hepatotoxicity attributable to HDSs prospectivelyenrolled into the DILIN over an 8-year period, the mostcommonly implicated products were supplements usedfor bodybuilding and for weight loss, representing31% and 18%, respectively, of the 93 collected cases(unpublished). Regarding the bodybuilding supple-ments, all were men who experienced characteristicallyprotracted periods of jaundice, with modest elevations inaminotransferase levels. In contrast, weight loss supple-ment injury occurred predominantly among females andwas characterized by more prominent elevations inaminotransferase levels.It seems prudent to distinguish between true herbaldrugs and dietary supplements, of which the lattermay or may not contain plant extracts, since the rea-sons for using each are different. Herbal drugs areused mostly to specifically treat or prevent certaindiseases, while dietary supplements are usually con-sumed to compensate for existing or presumed nutri-ent deficiencies or to promote health in general. Thus,the discussion on hepatotoxicity will be presented intwo sections, one focusing on herbal drugs for whichadverse hepatic drug reactions have been describedand the other describing nutritional supplements thathave been found causative for or associated withinstances of liver injury.CAUSALITY ASSESSMENT FORHEPATOTOXICITY DUE TO HERBALSAND DIETARY SUPPLEMENTSAs is the case for apparent liver injury from conven-tional medications and xenobiotics, there is no definitivemeans of diagnosing hepatotoxicity when the injury isthought to be attributable to HDS. Rather, an accuratediagnosis is predicated upon the clinician’s diagnosticacumen and on the willingness of the patient to be forth-coming about the use of products. Causality assessment,the process of determining whether there is a reasonablelikelihood that a drug or herbal or dietary supplement isthe cause of liver injury, is generally performed usingone of several methods [129À134]. More importantly, theassessment must be conducted in a carefully definedmethodical fashion (Fig. 35-1); the steps are similarwhether the suspect is a conventional medication or anherbal or dietary supplement, with only minor modifica-tion. First, when liver injury is identified, the initial stepis to obtain a thorough medical history surrounding theevent that must include information on the contempora-neous receipt of all medications as well as of HDSs. Anactive inquiry into the use of HDS is critical since, as hasalready been stated, patients frequently fail to divulgethe use of such products. Second, the use of a productmust obviously have preceded the onset of injury but, ingeneral, must have been started no more than a yearearlier. Third, all other causes of liver injury must beexcluded, including viral, autoimmune, hemodynamic/vascular, metabolic, and inherited diseases (Fig. 35-1).Fourth, attribution to a specific medicinal product issupported if there is improvement of the liver injuryfollowing cessation of the suspected product, referred toas dechallenge, with the caveat that, in rare instances, liverinjury can be self-perpetuating. Finally, perhaps the mostconvincing indicator for attribution of injury to a specificproduct is if there is recrudescence of the injury followingserendipitous or surreptitious resumption of that impli-cated product (rechallenge), often with a more vigorouspresentation and more severe outcome. However,because of the possibly greater severity of the reaction,routine intentional rechallenge cannot be advocated.A characteristic of drug-induced liver injury (DILI)that might be more helpful in implicating herbals thanconventional medications is the pattern (hepatocellu-lar, cholestatic, or mixed), duration, or severity of theobserved liver injury. For example, bodybuilding sup-plements have been reported on numerous occasionsto typically produce a cholestatic form of liver injury,characterized by protracted jaundice and liver biopsyfindings revealing little inflammation but prominentbile pooling [135À137]. Given this extensive clinicalexperience—the identification of cholestatic liver dis-ease in the setting of bodybuilding supplements—sucha presentation permits firmly establishing causationwith a high degree of confidence.LIMITATIONS OF CAUSALITYASSESSMENT FOR HEPATOTOXICITYDUE TO HERBALS ANDDIETARY SUPPLEMENTSAlthough several methods have been employed fordetermining causality for liver injury of conventional639LIMITATIONS OF CAUSALITY ASSESSMENT FOR HEPATOTOXICITY DUE TO HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 10. medications, there has not been a distinctive or formalmethod developed to assess causality for liver injuryattributable to HDS, although this is an issue of currentinvestigation [138]. Developing a more specific causal-ity assessment tool is important because there areseveral aspects of HDS use that can confound the pro-cess of causality assessment.One challenging issue faced in performing causalityassessment of possible HDS-induced liver injury is thepotential for batch-to-batch, seasonal, and geographicvariability in the composition of the product underconsideration. This can cause the problem of misattri-bution, even though the causality assessment processsuggests impugning a specific product, since the injuri-ous ingredient or combination of ingredients may nolonger be present.Establishing the timing and duration of use of anagent is an important aspect of determining causal-ity. Current methods of causality assessment assigna lower likelihood of attribution if the latencyperiod between starting the product and the firstevidence of liver injury is unusually prolonged.Because of the potential for variability of ingredientsfrom batch to batch or for the introduction of new,more potent ingredients at variable times after initi-ating treatment, a reliance on latency may notalways be relevant.Finally, many HDSs are complex mixtures, contain-ing a multiplicity of ingredients that make it nearlyimpossible to identify which specific ingredient is thecause of injury. There are also instances in which aningredient thought to be harmful is excluded from aproduct, yet injury from this product continues. Thisoccurred when liver injury was attributed to thecommercial product Hydroxycut; the toxic ingredientwas believed to be ephedra, which was thereforeordered by the FDA to be excluded from its formula-tions in 2003 [139À144]. However, cases of liver injurycontinued to occur, finally leading to its completemarket recall in 2009. Clearly, improved detectionmethods are needed to unequivocally identify the toxicingredient(s) in an herbal mixture responsible for caus-ing the liver injury.HERBAL PRODUCTS ASSOCIATEDWITH LIVER INJURYHerbals may damage the liver in a manner similarto that attributed to synthetic drugs and the liverinjury can be variable, even with the same herbal. Aswith conventional drugs, there is no uniform mecha-nism by which injury develops, and risk factors thatrender an individual susceptible to herbs are knownfor only a minority of preparations. Hence, clinicalsigns, symptoms, and findings are identical to thoseencountered when liver injury is due to syntheticdrugs. Clinicians are often misled by not inquiringabout the use of herbals and may therefore pursuefalse lines of suspicion, particularly, if patients do notadmit to taking herbals. Liver biopsy may be justifiedin some instances to assess the type and extent of liverinjury, especially when the presentation is that ofchronic liver disease, but liver histology lesions specificto herbals are only described for a very few remedies. Acareful medication history with specific interrogationfor the intake of natural, herbal, or unconventionalmedication is usually the key investigation, and manyViral Hepatitis Biliary ObstructionMetabolic/GeneticAnatomical LesionLiver InjuryHemodynamic ShockAutoimmune Disease-Ultrasound-MRCP-ERCP-Ferritin, iron, iron bindingcapacity-A1AT level and phenotype-Ceruloplasmin-Ultrasound/CT/MRI-AFP-CEA-Hypotension-Cardiac arrest-Vascular collapse-Hepatitis A lgM-Hepatitis Bsurface antigen-Hepatitis C antibody-Antinuclear antibody-Anti-smooth muscleantibody-Gamma globulinsPossible Hepatotoxicity-History of herbal or dietary supplement useFIGURE 35-1 The diagnosis of hepatotoxicitydue to herbal and dietary supplements dependsupon exclusion of other causes. These includeviral hepatitis, hemodynamic-shock, autoimmunedisease, biliary obstruction, metabolic and geneticdiseases, and anatomical lesions. It is only aftertaking such an approach, coupled with the appro-priate history of herbal or dietary supplement useprior to the onset of injury, that the diagnosis canbe made with confidence. A1AT, alpha 1 antitryp-sin; AFP, alpha-fetoprotein; CEA, carcinoembryo-nic antigen; CT, computed tomography; ECRP,endoscopic retrograde cholangiopancreatography;IgM, immunoglobulin M; MRCP, magnetic reso-nance cholangiography; MRI, magnetic resonanceimaging.640 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 11. published reports describe delayed recognition of her-bals as the true culprit in cases of DILI. A review of her-bals that have been associated with liver damage isprovided (Table 35-2).Herbals Containing Pyrrolizidine AlkaloidsAmong the first herbals found to occasionally causesevere hepatic injury were those containing pyrrolizi-dine alkaloids such as echimidine, monocrotaline,retronecine, seneciphylline, and symphytum. Extractsfrom Crotalaria, Heliotropium, Senecio, and Symphytum(comfrey) species are particularly hepatotoxic, with aclear dose dependency. Comfrey (Symphytum officinale)is traditionally used to externally treat bruises andjoint injuries with tinctures and ointments, but oralpreparations are banned in Europe and NorthAmerica. Exposure of humans to pyrrolizidine alka-loids occurs predominantly via contaminated food-stuffs such as salads, cereals, and honey [145]. As earlyas 1920, a syndrome of ascites, hepatomegaly, andeventually cirrhosis was described as Senecio diseasein South Africa [146], and was followed by reportsfrom Jamaica of children developing a similar diseaseafter the ingestion of bush tea, which containsCrotalaria species [147]. Contamination of cropswith Heliotropium was the reason for a series of pyrro-lizidine alkaloid poisonings in India [148,149] andAfghanistan [150], and was followed by instances ofliver damage from pyrrolizidine alkaloid intoxicationin Arizona, such as in two infants after drinkingherbal tea made of Senecio longilobus [151,152]. Similarcases have also been seen in Europe and elsewhere[153À155].The type of liver injury provoked by pyrrolizidinealkaloids is sinusoidal obstruction syndrome (SOS;also known as hepatic venoocclusive disease), a non-thrombotic obliteration of the sinusoids and lumen ofthe terminal centrilobular hepatic veins. The resultingvenous outflow obstruction causes hepatic congestionand parenchymal necrosis resulting in acute liver fail-ure (ALF) or liver fibrosis and cirrhosis [156]. Themechanism of injury involves a direct toxic effectrelated to biotransformation of pyrrolizidine alkaloidsby microsomal cytochrome P450 (CYP) enzymes intopyrrole derivatives, which then form genotoxic proteinadducts [157]. Notably, pyrrolizidine alkaloid toxicitycan be enhanced by phenobarbital, a potent inducer ofCYP3A4, CYP2B6, and several isoenzymes of the 2Cfamily. Acute toxicity is not species specific and ananimal model of SOS using monocrotaline has beencharacterized [158]. Abundant experimental data alsopoint to an oncogenic potential of comfrey andother pyrrolizidine alkaloid-containing herbs [159].Treatment of affected patients is symptomatic,and spontaneous recovery upon dechallenge to pyrro-lizidine alkaloids is possible; however, for thoseprogressing to acute or chronic liver failure, livertransplantation should be considered.Chinese HerbsIn TCM, the use of herbals dates back as far as 2100BC and, along with the rising popularity of orientalmedicine, their use is increasing worldwide. MostChinese medicines are mixtures of several differentherbs of which one or two are considered the pharma-cologically active King herbs, while the remaining con-stituents enhance the effect of the King herb, alleviatetoxicity, or support circumstances considered impor-tant for regaining health. More than 13,000 differentherbal preparations are used in TCM, which makesit extremely difficult to identify the componentresponsible for the liver injury. Active or toxic ingredi-ents may vary when plants are harvested duringdifferent seasons or extracted through variable proce-dures. Also, contamination of herbals with microor-ganisms, pesticides, heavy metals, fungal toxins suchas aflatoxin, and synthetic drugs has been described[160].In the United States, large-scale consumption of JinBu Huan (Lypocodium serratum) for mild sedativeeffects has precipitated a total of 11 cases of both acuteand chronic hepatitis [161,162]. Unlike many TCMherbal mixtures, Jin Bu Huan is an extract fromLypocodium serratum and (–)-tetrahydropalmitine is theactive ingredient, with opiate-like properties. The pre-cise mechanism by which liver injury is precipitated iscurrently unclear, but (–)-tetrahydropalmitine is struc-turally similar to pyrrolizidine alkaloids (see above).However, liver histology in patients who took Jin BuHuan showed focal necrosis and portal fibrosis, but novascular lesions. In all published cases, increased ami-notransferase levels have normalized after treatmentdiscontinuation.A number of dietary products marketed in theUnited States contain ma huang (Ephedra spp.) to sup-port weight reduction. Apart from cardiotoxicity, sev-eral published reports provide evidence for the risk ofhepatotoxicity following the ingestion of ma huang[163À166]. Typically, acute hepatitis occurs after ashort period of intake, sometimes with elevated auto-antibodies, suggesting drug-induced autoimmunity.Alternatively, Bajaj et al. have suggested that mahuang hepatotoxicity may be associated with com-pound heterozygosity for mutation in the HFE gene(encoding the hereditary hemochromatosis protein),possibly via enhancing oxidative stress [164].641HERBAL PRODUCTS ASSOCIATED WITH LIVER INJURYIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 12. TABLE 35-2 Herbal Remedies Associated With Liver DamageHerbal Application Toxin Toxic Mechanism Clinical PresentationPyrrolizidinealkaloids:Herbal tea,contamination offlour/cropToxic pyrroles Toxification of pyrrolizidinealkaloids by CYP3A4Sinusoidal obstructionsyndrome (venoocclusivedisease)SymphytumofficinaleCrotalariaSenecio longilobusHeliotropiumChinese herbalcombinations:Paeonia spp. Immunostimulation,Atopic dermatitisUnknown Unknown Acute and chronicHepatitis, hepatic failureDictamnusdasycarpusJin Bu Huan Sedative Lypocodium serratum Contains(À)-tetrahydropalmitinewith structural similaritiesto PAAcute and chroniccholestatic hepatitis,fibrosisMa huang Weight reduction Ephedra sinica (ephedrine) Immunoallergic? Acute hepatitis,autoimmune hepatitisShou Wu Pian Liver tonic, dizziness,hair loss, constipationPolygonum multiflorum Anthraquinone conversionto hepatotoxin rheinAcute hepatitisOnshidou-Genbi-KounouWeight reduction Unknown; contains Amachazuru tea leaf,barbaloin, saponins, polyphenolsUnknown Acute hepatitis, liverfailureChi R Yun Venereal diseases,contusion, heartfailure, growthretardationBreynia officinalis Unknown ÀGermander:TeucriumchamaedrysWeight reduction Neoclerodane diterpenoids Hepatocyte apoptosis Acute and chronichepatitis (including liverfailure), fibrosis (whenchronic)Teucrium polium Antiinflammatory Unknown Unknown ÀChaparral(Greasewood)Larrea tridentataAntioxidant, liverand health tonic,snake bitesNordihydroguaiaretic acid Inhibition of COX-1/2 andseveral cytochrome P450sCholestasis, cholangitis,chronic hepatitis,cirrhosisAtractylis gummifera Antiemetic, diuretic,chewing gumAtractylosides Inhibition ofgluconeogenesis throughinterference with oxidativephosphorylationAcute hepatitis, liverfailureCallilepis laureola(Impila)Miscellaneous, Zuluremedy (SouthAfrica)Atractylosides Like Atractylis gummifera Like Atractylis gummiferaPennyroyal oil Abortifacient,pesticideMenthofuran Glutathione depletionthrough electrophilicmetabolitesFulminant hepatic failureGreater celandine Irritable bowelsyndromeUnknown Drug-inducedautoimmunity?Chronic hepatitis, fibrosischolestatic hepatitis,(Continued)642 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 13. Several cases of acute hepatitis and even fulmi-nant hepatic failure have been reported in studiesthat have investigated the efficacy of Chineseherbal preparations for treating atopic dermatitis[167,168]. The investigators failed to identify thecausative agent, but many herbal combinations usedto treat eczema have contained Paeonia and/orDictamnus dasycarpus. It is noteworthy that of the sixcases reported with D. dasycarpus, two were fatal[169].The Shou Wu Pian remedy formulated from the rootsand vines of Polygonum multiflorum is used as a treat-ment for dizziness, hair loss, constipation, and, interest-ingly, as a liver tonic. It was first identified in 1996 tohave caused acute hepatitis in a 31-year-old pregnantwoman, the liver disease subsiding completely after dis-continuation of the herb [170]. Following this, there havebeen additional reports of its potential to cause liverinjury [171À175]. Toxicity could be the result of anthra-quinones, which are known to be constituents ofTABLE 35-2 (Continued)Herbal Application Toxin Toxic Mechanism Clinical PresentationKava Anxiolytic, sleepingaidKava lactones (kavain, dihydrokavain)? Idiosyncratic, dose-dependent toxicity?Acute and chronichepatitis, cholestasis,liver failureBlack cohosh(Cimicifugaracemosa)Menopausalcomplaints, joint andmuscle painUnknown Liver cell apoptosis viamitochondrial damageMild liver enzymeelevations, acutehepatitis, liver failureSenna (Cassiaangustifolia)Laxative Unknown Unknown Cytolytic hepatitisCascara sagrada Laxative Anthracene glycosides Cholestatic hepatitisthrough unknownmechanismCholestatic hepatitisSaw palmetto Prostatism Serenoa repens or serrulata Unknown Mild hepatitisCentella asiatica Multiple Unknown Saponins? Granulomatous hepatitis,cirrhosisNoni (Morindacitrifolia)Health tonic Unknown Anthraquinones? Acute cytolytic hepatitis,liver failureCamphor Rubefacient Cyclic terpenes Unknown Necrolytic hepatitisIsabgol Laxative Unknown Unknown Giant cell hepatitisMargosa oil(Azadirachta indica)Health tonic Unknown Mitochondrial damage Reye syndromeOil of cloves Dental pain Eugenol Dose-dependenthepatotoxinHepatic necrosisValerian (Valerianaofficinalis)Sedative Unknown Unknown Mild hepatitisGreen tea (Camelliasinensis)Standard beverage (2)-Epigallocatechin gallate or itsmetabolite (2)-epicatechin gallateOxidative stress-relatedcytotoxicityAcute hepatitis,cholestasisHerbalifenutritionalsupplements(numerousproducts)Weight loss, dietarysupplement forbalanced nutritionUnknown Idiosyncrasy?;contamination withbacteria?Cytolytic and mixedhepatitis, fulminanthepatic failureUsnic acid Weight loss Contains norephedrine hydrochloride,caffeine, diiodothyronine, yohimbinehydrochlorideUnknown; uncoupling ofrespiratory chain andmitochondrial damage?Acute liver failureHydroxycut Weight loss,bodybuildingContains Garcinia cambogia (Garciniagummi-gutta), Gymnema sylvestre,chromium polynicotinate, caffeine,green teaUnknown Acute cytolytic hepatitis,liver failureCOX, prostaglandin G/H synthase.643HERBAL PRODUCTS ASSOCIATED WITH LIVER INJURYIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 14. P. multiflorum. Anthraquinones are metabolized bycolonic bacteria to highly reactive anthrones that, whenabsorbed and transported to the liver, may cause liverdamage [176].Another herbal marketed for weight loss, Onshidou-Genbi-Kounou, combines several natural compounds(amachazuru, barbaloin, polyphenols, tealeaf, and totalsaponin), and was the suspected cause of severe acutehepatitis followed by hepatic failure in a woman whotook this preparation for several months [177]. Serumlevels of liver enzymes were massively elevated to.9,000 IU/L and coagulopathy developed; however,the patient recovered upon cessation of drug intake.Onshidou-Genbi-Kounou contains N-nitrosofenflura-mine, which has only been associated with valvularheart disease. Possibly, Onshidou-Genbi-Kounou con-tains further unknown hepatotoxins.Breynia officinalis is marketed under the Chineseproprietary name, Chi R Yun, and is used to treat con-junctivitis, contusions, growth retardation, heart fail-ure, and venereal diseases, in combination with otherTCMs. Following the report to the Poison ControlCenter of Taiwan of the first two cases of liver injuryfrom this herbal, one involving a 43-year-old womenwho attempted to commit suicide and developed acutecytolytic hepatitis and the other a 51-year-old womanwho used the product to treat her contact dermatitis[178], a case series was described of 19 poisonings thatoccurred when soup was cooked with B. officinalis,accidentally mistaken for a similar plant, Securinegasuffruticosa. The affected persons developed diarrhea,nausea, vomiting, and hepatocellular liver injury with-out jaundice within 6 months of consuming the soup[179]. The exact mechanism of liver injury remainsundetermined, but the close temporal relationship anda positive dechallenge response identifies B. officinalisas the likely cause of liver injury in these cases.GermanderGermander (Teucrium chamaedrys)-containing cap-sules and tea bag preparations were approved asweight loss remedies in France, although its activeingredients and precise mechanism of action remainunknown. Subsequent widespread use led to severalreports to the French Pharmacovigilance Authorities in1992 about germander-associated acute, chronic, andeven fulminant hepatitis [180]. Liver injury usuallydeveloped 2 months after intake and, in those with anacute pattern of liver enzyme alterations, acute cyto-lytic hepatitis was found histologically. Some patientswith a chronic course of liver disease showed histolog-ical features of chronic hepatitis with fibrosis and evencirrhosis. Causality assessment linking germander andliver damage was confirmed after accidental reexpo-sure led to an immediate relapse of liver injury.However, all patients recovered after discontinuationof the herbal, except for those with cirrhosis.Systematic analysis of germander preparations demon-strated that they contained flavonoids, glycosides,saponins, and several furane-containing neoclerodanediterpenoids [166]. Regarding the latter, animal experi-ments have demonstrated the formation of toxic andhighly reactive epoxides from these diterpenoids,which are potent inducers of hepatocyte apoptosis[181À184]. Formation of epoxides is enhanced by theinduction of CYP3A and by glutathione (GSH) deple-tion, which may occur during weight loss or regularalcohol consumption.Subsequently, there have been reports of fulminanthepatic failure following the ingestion of Teucriumpolium used as an antiinflammatory and antimicrobialdrug and for the treatment of scars [185,186]. There isalso a single report of acute hepatitis with jaundicethat occurred in a patient who took a traditionalChinese remedy containing Teucrium viscidum for backpain and that resolved spontaneously after the remedyhad been stopped [187].ChaparralChaparral (Larrea tridentata; commonly referred toas creosote bush or greasewood) grows in deserts and is atraditional herbal remedy among Native Americans totreat the common cold, bone and muscle pain, andsnake bites. Commercial products containing chaparralhave been sold for weight reduction and for allegedantiinflammatory, antioxidant, and blood-purifyingactivities. Furthermore, chaparral has been part of theself-medication taken by patients with HIV infection[188]. In the 1990s, the FDA recorded a series of casesof chaparral-related hepatotoxicity ranging from mildelevations of serum liver enzyme concentrations to ful-minant hepatitis, with subsequent liver transplantationfor hepatic failure in two cases [189]. Although chole-static hepatitis accounted for the majority of cases,there were also instances in which cirrhosis developed.L. tridentata was found in all preparations, and bio-chemical and microbial contamination was excluded.A causal relationship was postulated based on thetemporal correlation between intake of chaparral andthe onset of liver disease, a consistent pattern ofhepatic damage, and the observation that reexposureto chaparral or an increased dose led to relapse oraggravation of clinical signs of liver disease. Chaparraltoxicity is believed to be due to nordihydroguaiareticacid, which inhibits prostaglandin G/H synthases(COX enzymes) and CYP [190].644 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 15. Atractylis gummifera and Callilepis laureolaAtractylis gummifera has been traditionally used as anatural antipyretic, diuretic, and emetic in NorthAfrica and the Mediterranean, and a secretion fromthe plant is occasionally consumed by children aschewing gum [191,192]. Toxic hepatitis with an acuteonset is well known and commences a few hours afteringestion, accompanied by abdominal pain, headache,and nausea. It is associated with a syndrome of neuro-vegetative symptoms, hepatorenal failure, and pro-nounced hypoglycemia [193]. Death due to fulminanthepatic failure is a possibility. Consumption of A. gum-mifera is particularly dangerous during springtime,when toxins are highly concentrated in roots, or whenthe plant is confused with wild artichoke.Callilepis laureola is the major constituent of Impila—a traditional herbal remedy used among the Zulu peo-ple from South Africa as a multipurpose treatment forstomach problems, impotence, infertility, and to deterevil spirits. Paradoxically, Impila is the Zulu word forhealth. However, numerous reports provide substantialevidence for potentially fatal nephro- and hepatotoxic-ity of C. laureola[194]. For example, a large series ofchildren were identified retrospectively as having diedfrom C. laureola intoxication, presenting with a clinicalpattern similar to Reye syndrome with acute hepatore-nal failure, hypoglycemia, and multiorgan hemorrhage[195]. Toxicity begins with a sudden onset and mortal-ity is high. Autopsy examinations show centrilobularzonal necrosis of the liver, tubular renal necrosis, andhemorrhages in lungs, skin, and intestine. Despite itswell-known toxicity, the underlying mechanism isonly partly understood. Studies in rats indicate thatatractyloside and carboxy-atractyloside are potent in-hibitors of oxidative phosphorylation and other mito-chondrial functions, leading to apoptosis [196]. Popatet al. have shown that Impila extracts cause a concen-tration- and time-dependent loss in viability andmitochondrial GSH content in HepG2 cells that ispreventable with N-acetylcysteine and S-adenosyl-L-methionine, which are precursors of GSH [197].PennyroyalPennyroyal, also referred to as squawmint oil, is anherb containing leaves from either Mentha pulegium orHedeoma pulegioides that has long been identified as acause of severe acute liver injury [198]. Its traditionaluse is as a natural abortifacient and deterrent againstfleas. Several reports of fulminant hepatic necrosis dueto pennyroyal with lethal outcome have beendescribed [199,200]. Its primary constituents are pule-gone and various other monoterpenes characteristi-cally contained in mint species, and particularly inpennyroyal. Hepatotoxicity appears to be due to deple-tion of GSH by pulegone, subsequently enhanced oxi-dative stress, and via the primary metabolite ofpulegone, menthofuran, which is transformed throughCYP into a hepatotoxin [200À203].Greater CelandineDrugs containing greater celandine (Chelidoniummajus) are used in Europe to improve bile flow andirritable bowel syndrome. Greater celandine containsat least 20 different alkaloids, including berberine, che-lerythrine, coptisine, and chelidonine, of which the lat-ter serves to standardize the extract [204]. However,the therapeutic efficacy of greater celandine for theseindications has never been tested in controlled trials.Several reports from European countries, where com-mercial drug preparations containing greater celandinealkaloids are widely available, have described poten-tial hepatotoxicity of this herbal [204À207]. The largestseries of 10 patients from a single German centerrevealed cholestatic hepatitis together with low titersof autoantibodies, suggesting drug-induced autoimmu-nity after variable periods of ingestion of differentgreater celandine preparations [208]. However, theexact mechanism responsible for injury remainsunclear and efforts to replicate hepatotoxicity inexperimental animals have thus far failed.KavaIn industrialized countries, kava-containing prep-arations are marketed for the treatment of anxiety dis-orders and depression, while kava root (Pipermethysticum rhizoma) has long been used as a tradi-tional psychotropic remedy in Hawaii, Polynesia, andthe Fiji Islands. Its sedative activity is causedby kavapyrones, including kavain, dihydrokavain,methysticin, and dihydromethysticin, which act asgamma-aminobutyric acid receptor agonists, thus inhi-biting activating neurons in the reticular formationand the limbic system [209À210]. A recent systematicreview and meta-analysis of randomized, controlledtrials with kava for the treatment of anxiety showed asignificant anxiolytic effect, as assessed by theHamilton Rating Scale for Anxiety, as well as good tol-erability [211]. More than 100 cases of liver damagehave now been associated with the intake of kavaworldwide, comparable to numbers that have led tothe banning of synthetic drugs [212]. Consequently,the license to distribute kava products was revokedin the United States, Europe, and Australia [213].A detailed analysis of 29 cases of adverse hepatic reac-tions due to kava in Germany using a clinical causality645HERBAL PRODUCTS ASSOCIATED WITH LIVER INJURYIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 16. score reported liver injury with both alcoholic and ace-tonic kava extracts [214]. The large majority of patientswere females who developed cytolytic or cholestatichepatitis, and nine patients who developed fulminantliver failure with subsequent liver transplantation ineight of the patients: three patients died, two followingunsuccessful liver transplantation, and the remainingpatients recovered completely after the withdrawal ofkava. The mechanism by which liver injury is precipi-tated remains unclear, since no dose-response patterncan be recognized. However, some patients took dosesexceeding several times the recommended daily doseof 120 mg. For most other patients, both the cumula-tive dose and the latency until the hepatotoxic reactionemerged were highly variable, suggesting drug idio-syncrasy. Along this line, a poor-metabolizer pheno-type of CYP2D6 was suggested to be a risk factor fordeveloping kava-related liver damage [215]. Anotherpossible basis for its toxicity relates to the mode ofkava extraction, with recent in vitro and animal studiesconfirming that aqueous kava extracts are less cyto-toxic than are organic solvent fractions [216,217].Notably, modern commercial products rely on alcoholor acetone extraction, a process that may extract toxiccompounds (e.g., alkaloids) from the plant.Black Cohosh (Cimicifuga racemosa)Black cohosh, a popular herbal from North Americafor the treatment of menopausal symptoms, joint pain,and myalgia, has been implicated in a number of casereports on liver injury in Australia and North America[218À220]. Clinical presentation ranges from mildserum aminotransferase elevations to fulminanthepatic failure. In several cases, urgent liver transplan-tation was necessary. Some patients present withfeatures resembling autoimmune hepatitis, such as ele-vated autoantibodies or skin rashes. In response tothese reports, the Dietary Supplement InformationExpert Committee of the US Pharmacopeia’s Councilof Experts analyzed information from human clinicalcase reports, adverse event reports, animal pharmaco-logical and toxicological data, historical use, regulatorystatus, and contemporaneous extent of use associatedwith black cohosh [221]. All 30 individual reports ofliver damage were assigned a causality score of possi-ble, but none was labeled as probable or certain. Basedon these results, the Dietary Supplement InformationExpert Committee determined that black cohosh prod-ucts should be labeled with a cautionary statementindicating that hepatotoxicity is a possible adverse out-come. Although meta-analysis of five randomized,controlled clinical trials, including .1,000 patients,revealed no evidence of liver toxicity [222], andreanalysis of individual case report information withliver-specific causality scores raised doubts over blackcohosh as being truly hepatotoxic [223], a low inci-dence of black cohosh hepatotoxicity cannot beexcluded by these data. How toxicity may occur is notfully elucidated, but experimental data indicatemitochondrial damage and subsequent apoptosis as apossible molecular mechanism [224].MiscellaneousVarious other botanicals have been associated withtoxic liver damage, such as senna (Cassia angustifolia),which is used as a laxative. Senna was identified asthe cause of relatively benign hepatitis in a womantaking approximately 10 times the recommended dose[225]. Causality was confirmed by positive rechallenge.Nadir et al. described a man in whom short-termuse of a commercial Cascara sagrada product causedcholestatic hepatitis with subsequent portal hyperten-sion, prolonged prothrombin time, and ascites [226].C. sagrada contains anthraquinone glycosides and isrecognized as an effective laxative. Other frequentetiologies were excluded, but the patient also tookamitriptyline, baclofen, and cimetidine at recom-mended doses, which can occasionally cause liverinjury. Further laboratory tests revealed elevated anti-nuclear and anti-smooth muscle antibody titers of1:640 and 1:40, respectively, and liver biopsy showedan eosinophilic infiltrate, suggesting drug-inducedautoimmunity.Also, a combination of herbal ingredients, known asProstata, was suspected to have caused cholestatichepatitis in a man using this medication for thetreatment of benign prostatic hyperplasia [227].The presumed active ingredient is Serenoa serrulata,which exerts estrogenic and antiandrogenic effects.Either hormone may cause liver injury under certaincircumstances.Centella asiatica has been used in Ayurvedic medi-cine as a psychophysical regenerator and blood purifier,and for the treatment of dementia, diabetic microan-giopathy, skin defects, and obesity [228]. Recently,three female patients who took this herbal for periodsof between 1 and 6 months to lose weight developedsevere hepatic injury, including granulomatous hepati-tis and cirrhosis [229]. Unintentional reexposureresulted in accelerated recurrence of hepatic lesions intwo of the patients. Extracts of this herb contain penta-cyclic triterpenic saponosides, including asiaticoside,madecassoside, and centellasaponins. The mechanismby which liver damage is precipitated is uncertain.Treatment with ursodeoxycholic acid at 10 mg/kg/dayled to normalization of altered liver biochemistries in646 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 17. all three patients. Another Ayurvedic herbal prepara-tion, termed Liv.52, is freely available through Internetsources and health food stores across North Americaand Europe, and is taken to strengthen the liver and toinfluence the natural course of chronic liver diseases.Liv.52 contains Achillea millefolium (yarrow), Capparisspinosa (capers), Cichorium intybus (wild chicory),Solanum nigrum (black nightshade), Terminalia arjuna(arjuna), and others. Liv.52 has been suggested asuseful for the treatment of human alcohol-related livercirrhosis after experimental data suggested that it mayreduce acetaldehyde production [230]. A Europeanrandomized controlled clinical trial in 188 patientswith alcoholic liver cirrhosis showed no benefit onsurvival and on surrogate markers of liver injury incirrhotics with Child-Pugh class A and B, and thestudy was prematurely terminated because ofincreased liver-related mortality among those withChild-Pugh class C [231].A recent case series of seven patients suggests possi-ble liver toxicity from Noni juice (Morinda citrifolia),leading to liver failure requiring liver transplantationin one case [232,233]. Other possible causes for theacute hepatitis were ruled out and liver tests rapidlyreturned to normal after the cessation of Noni intake.Active components within Noni extracts includeflavonoids, glycosides, polyunsaturated fatty acids,vitamins, and anthraquinones. The latter can be trans-formed into rhein by intestinal bacteria and causemitochondrial damage [234]. However, experimentalstudies with Noni have failed to reproduce hepatotox-icity in vitro and in vivo [235].DIETARY SUPPLEMENTS ASSOCIATEDWITH LIVER INJURYGreen Tea (Camellia sinensis)Green tea has been consumed for centuries and iscurrently among the most popular drinks in the world.The first report on liver injury following the ingestionof green tea extracts and preparations was publishedin 1999 [236] and, since then, there have been numer-ous cases reported to regulatory agencies worldwide.In response, the US Pharmacopeia performed a sys-tematic review of all reported and published casesfrom North America, Great Britain, and Australia ofliver injury following the ingestion of various differentgreen tea preparations [237]. Thirty-four case reportswere retrospectively evaluated, and seven reports per-taining to liver damage were labeled as probably, andthe remaining seven cases as possibly linked to greentea. Subsequently, additional cases were made publicand, to date, there have been 58 case reports recordedof hepatotoxicity associated with the consumption ofgreen tea extracts, powdered leaves, green tea infu-sions, and hydroalcoholic and aqueous extracts [238].Of particular concern is that these included one lethalcase. On histological examination, the livers of patientsrevealed necroinflammatory changes and cholestasis.However, caution should be exercised about assigningunequivocal blame for the liver injury on green tea insome of the reported cases, since in many instances thepatients also took other products that have been impli-cated in causing hepatotoxicity such as C. angustifolia(see above), Ephedra sinica, and Hydroxycut (for both,see below). The basis for the toxicity caused by greentea is uncertain but could be due to (2)-epigallocate-chin gallate or its metabolite (2)-epicatechin gallatewhich, under certain conditions such as fasting, caninduce liver damage via increasing oxidative stress[239]. In contrast, however, in vitro and in vivo experi-mental studies have also demonstrated hepatoprotec-tive properties for green teas [240À242], and a recentsystematic review of clinical studies aimed at definingthe therapeutic effects of C. sinensis in humans foundoverall favorable effects from the tea as reflected byreduced mortality, attenuated steatosis, and a reducedincidence of primary liver cancer [243]. Currentevidence suggests a causal relationship between intakeof green tea-containing products and hepatotoxicity,and whether the risks from green tea consumptionoutweigh their benefits remains open to speculation.Consequently, in their systematic review, the USPharmacopeia included a cautionary statement aboutgreen tea that reflects this uncertainty [237].HerbalifeThere are six published reports describing 34 casesfrom Argentina, Iceland, Israel, Spain, and Switzerlandof severe liver injury following consumption ofHerbalife nutritional and herbal supplements forweight control and improvement of nutrition[244À249]. The patterns of injury were mostly hepato-cellular, but mixed and cholestatic enzyme patternswere also noted, with severity ranging from mild tosevere hepatic damage, including evidence of cirrhosisand ALF requiring liver transplantation. Generallyaccepted liver disease assessment scoring systemswere used in evaluating most of the cases, five ofwhich scored as certain because of a positive rechal-lenge, while most of the remainder were judged asprobable. The cause of liver damage remains specula-tive, since the patients took up to 17 differentHerbalife products at the same time. In addition to thepossibility that autoimmune mechanisms played a rolein inducing the liver injury among those who had647DIETARY SUPPLEMENTS ASSOCIATED WITH LIVER INJURYIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 18. elevated titers of autoantibodies and plasma cell infil-trates in their liver biopsies, adulteration of individualbatches with bacterial pathogens may explain someother cases, in view of a report that two patients werefound to have bacterial contamination of severalHerbalife products with Bacillus subtilis and Bacilluscereus [248]. Herbalife runs numerous production sitesworldwide, suggesting that spoiled products contami-nated with certain germs, chemicals such as softeners,preservatives, and flavor enhancers, pesticides, orheavy metals either added intentionally during themanufacturing process or accidentally contained in theunrefined raw products, i.e., the herb extracts, couldhave been responsible for local series of cases ofhepatotoxicity.Usnic AcidUsnic acid extracted from lichens and fungi havebeen marketed as dietary supplements in the UnitedStates to aid in weight loss. Efficacy for this indicationwas postulated based on its function as an uncouplerof the respiratory chain, which in principle can aug-ment weight loss but also cause mitochondrial damageand subsequent hepatocyte death [250]. Several casesof ALF have been reported requiring liver transplanta-tion following the intake of Lipokinetix, a product con-taining usnic acid and sold as dietary supplementcapsules [165,251À254]. In reacting to these reports,the FDA issued a warning about Lipokinetix in 2001[255]. Onset of liver injury was usually acute with amaximum latency of 3 months and the injury patternwas hepatocellular with massive elevations of alanineaminotransferase and aspartate aminotransferase.Apart from usnic acid, Lipokinetix contained caffeine,diiodothyronine, norephedrine hydrochloride, andyohimbine hydrochloride, which were confirmed byanalyzing the used Lipokinetix lots. None of the ingre-dients was previously associated with liver damageand inadvertent contamination was excluded. Theseserious events caused the withdrawal of Lipokinetixfrom the market.HydroxycutOwing to numerous reports of liver injury, includ-ing cases with acute hepatic failure and subsequentliver transplantation, several Hydroxycut productscontaining caffeine, chromium polynicotinate, Garciniacambogia (Garcinia gummi-gutta), Gymnema sylvestre,and green tea were withdrawn by the manufacturerfollowing a warning posted by the FDA in May 2009[140À145,256]. Hydroxycut preparations were soldto support weight loss and muscle building byconventional retailers, through Internet sources, andvia direct television marketing. The clinical presenta-tion consisted of an acute onset after several weeks ofintake, presenting with high levels of serum amino-transferases in the majority of cases, while others pre-sented with a more insidious, usually cholestaticcourse.NATURAL TOXINSWhile not ingested intentionally or deliberatelyadded to HDS, certain toxins derived from plants ornatural products might contaminate supplements orfood during preparation, processing, or storage thatmay occasionally cause liver injury if ingestedaccidentally.AflatoxinsHumans, particularly those in developing countrieswith humid climate conditions, such as sub-SaharanAfrica and East Asia, may be highly exposed to afla-toxins through consumption of maize (corn), peanuts,rice, and other crops contaminated with Aspergillusflavus or Aspergillus parasiticus. Acute aflatoxicosispresents with abdominal pain, diarrhea, and vomiting,thus rendering aflatoxin poisoning indistinguishablefrom acute gastroenteritis. Aflatoxins in doses of2À50 mg daily have been reported to cause acute toxichepatitis characterized by jaundice, ascites, portalhypertension, and encephalopathy associated with ahigh mortality [257À259]. The liver biopsy findings inthis situation include fatty infiltration and hepaticnecrosis, sometimes accompanied by bile duct injury.In addition to causing acute hepatotoxicity, aflatoxinsare potent carcinogens, well known to be associatedwith the development of primary HCC, but also withcancer of the kidneys and large bowel. Because theincidence of HCC is observed to be high in the sameregions in which aflatoxin exposure is common, effortsbegan in the 1960s to determine whether there was apossible link between the HCC risk and aflatoxinexposure. Not only did epidemiological data confirmthis association [260] but early experimental studies ofA. flavus-contaminated groundnut extracts also demon-strated that aflatoxins are in fact capable of inducingacute liver disease in ducks and liver cancer in rodents[261,262]. Indeed, aflatoxin-related hepatocarcinogeni-city occurs not only in humans but also in many otherspecies including dogs, nonhuman primates, rodents,and even fish [263]. Chemically, there are four differ-ent naturally occurring aflatoxins: AFB1, AFB2, AFG1,and AFG2. AFB1 and AFG1 possess an unsaturated648 35. HEPATOTOXICITY OF HERBALS AND DIETARY SUPPLEMENTSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 19. bond at the 8,9 position on the terminal furan ring,and epoxidation at this position appears to be criticalfor their hepatocarcinogenic potency [264].The metabolism of aflatoxin and the mechanisms ofaflatoxin-induced hepatocarcinogenesis are well docu-mented [265]. AFB1 requires metabolic activation to itsultimate carcinogenic form, primarily by the CYP mono-oxygenase system with the isoenzymes CYP1A2 andCYP3A4 that transform AFB1 to a reactive epoxide (afla-toxin-8,9-epoxide). The epoxide interacts with DNA togenerate a promutagenic aflatoxin-N7-guanine adductand, thus, a mutation in codon 249 of the p53 tumor sup-pressor gene that is considered crucial for the initiationof human hepatocarcinogenesis [266]. Although the epi-demiologic pattern of HCC is changing, i.e., beginning todecline in areas of the world of high HBV endemicitywith the advent of the hepatitis B vaccine and possiblyincreasing in areas plagued by the epidemic of obesityand diabetes, the primary causal risks worldwide con-tinue to be both HBV and HCV infections, as well asexposure to aflatoxin [267]. Indeed, aflatoxin exposure isstill considered a major cause of the differences in life-time HCC risks between Western countries and SouthEast Asia and Africa [267].Ackee FruitAckee fruit (Blighia sapida) poisoning has been occa-sionally reported in different developing countries,including Africa, Latin America, and the West Indies[268À270].Ackee fruits derive from large green leafy trees ofWest African origin and are consumed either raw orafter boiling in milk or water and served on their ownor in meat or fish dishes, such as ackee and salt fish.Ackee fruit is a substantial part of the diet in poor,agricultural areas and its taste resembles that of hazel-nut or avocado. Toxicity is related to hypoglycin Aand hypoglycin B, the former molecule being moretoxic than the latter. The ripe fruit flesh of ackeecontains only low quantities of hypoglycins, butconcentrations in unripe fruits are 10À100 timesgreater, depending on the season and exposure tosunlight, which significantly reduces hypoglycin con-centrations. In view of several larger series of intoxica-tions in Jamaica in the past, the disease related toackee fruit poisoning is also termed Jamaica vomitingsickness, with a clinical pattern similar to Reye syn-drome that includes gastrointestinal symptoms,marked hypoglycemia, and central nervous systemabnormalities that typically develop within 6À48 h ofingestion [271]. Lethality is high, particularly in infantsand children. Toxicity is believed to be related tomethylenecyclopropylacetic acid, a toxic hypoglycinmetabolite that interferes with several cofactors [e.g.,coenzyme A (CoA) and carnitine] essential to theβ-oxidation of long-chain fatty acids and thus inhibitsthe transport of long-chain fatty acids into the mito-chondria. The reduction in fatty acid metabolismcauses an increased use of glucose, and the blockadeof the substrate for hepatic gluconeogenesis causeshypoglycemia after the depletion of NADH andhepatic glycogen stores [271]. Findings at postmortemexamination of fatal ackee fruit intoxications haveincluded massive steatosis of the liver and kidney,depletion of liver glycogen, diffuse hemorrhages,and generalized hyperemia of the internal organs.Diagnosis is based on the patient’s history of the use ofthe product and the clinical presentation, since there areno specific biomarkers. There is no definitive therapyfor this poisoning other than the use of symptomaticmeasures such as fluid and glucose replacement. In thelight of these risks, ackee fruit is banned in the UnitedStates and other Western countries.Bacillus cereusThere are several case reports of fulminant liver fail-ure attributed to Bacillus cereus food poisoning[272À274]. B. cereus is a ubiquitous, endospore-form-ing, aerobic, gram-positive bacterium known for pre-cipitating a type of toxin-mediated food poisoning inthe Far East, typically after the ingestion of cookedrice. Although instances of fulminant hepatic failureare extremely rare, those reported have been well char-acterized, describing acute-onset hepatic failure com-plicated by lactic acidosis, rhabdomyolysis, cerebraledema, and death in some cases, despite maximalmedical care. Certain strains of this bacterium secrete acyclic peptide toxin, cereulide, which causes vomitingin humans and animals but may also act as a mito-chondrial toxin that interferes with fatty acid metabo-lism, leading to the breakdown of mitochondriaderived energy supply [274,275]. Thus, the pathophysi-ology of B. cereus-related liver failure is similar to thatobserved with ackee fruit, aflatoxin (see above), Reyesyndrome, and fatty liver of pregnancy [276].Diagnosis is based on the coexistence of fulminanthepatic failure, hypoglycemia, lactic acidosis, hyper-ammonemia, and central nervous system symptomsand should prompt immediate referral to a liver trans-plant center, since liver transplantation may be theonly therapeutic option for some patients.MicrocystinsWater contaminated with cyanobacterial hepatotoxicheptapeptides, i.e., microcystins, has been recognizedas a possible cause of an outbreak of ALF at a dialysis649NATURAL TOXINSIII. HEPATOTOXICITY OF SPECIFIC DRUGS
  • 20. center in Caruaru, Brazil [277]. At the clinic, 116 out of131 patients (89%) experienced visual disturbances,nausea, and vomiting after routine hemodialysis treat-ment. Subsequently, 100 patients developed ALF and,of these, 76 died. The observed syndrome was thustermed the Caruaru syndrome. Examination of phyto-plankton from the dialysis clinic’s water source and in-depth analyses of the clinic’s water treatment system,together with studies on serum and liver tissue ofclinic patients, led to the identification of two groupsof cyanobacterial toxins: the hepatotoxic cyclic peptidemicrocystins and the hepatotoxic alkaloid cylindro-spermopsin. Authors of this and subsequent analysesconcluded that the likely cause of liver injury weremicrocystins, specifically microcystin-YR, -LR, and-AR [278]. Cyanotoxins—to which class microcystinsbelong—are also implicated in animal poisoning,human gastroenteritis, dermal contact irritations, andprimary liver cancer in humans [279,280]. The (geno)toxic mechanism of microcystins is to act as potentinhibitors of protein phosphatase 1 and 2A, thus lead-ing to increased protein phosphorylation causing cyto-toxicity and tumor promotion [281].CONCLUSIONSHDS use is extensive, rivaling and often exceedingthat of conventional medications. There is generalbelief that because they have been used for centuriesand are pure, they must be effective and safe.Unfortunately, neither of these generalizations isaccurate. Efficacy for most herbal products has notbeen scientifically proven and they are certainly nosafer than conventional medications; some of them areless safe. Safety would be enhanced if there weregreater oversight of their production and distributionto ensure that they do not contain potentially toxic orotherwise dangerous contents. 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