Complementary therapies

Objectives: To investigate complementary and alternative medicine (CAM) use by patients with chronic obstructive pulmonary disease (COPD) and to explore their beliefs about CAM.Design and participants: Cross-sectional study of 173 patients with moderate to severe COPD, and indepth interviews with a purposive sample of 28 patients.Setting: Ambulatory care.Main outcome measures: Use of CAM; beliefs about the value of CAM.Results: 71 patients (41%) claimed to be using some form of CAM. Most commonly used were multivitamins and minerals, and garlic was the most commonly used herbal preparation. Patients reported that advertisements and people with prior experience of using CAM were their major sources of information. Extent of knowledge about CAM, degree of faith in CAM and personal attitudes influenced decisions to try CAM. Patients used CAM to promote general wellbeing, to counteract drug side effects, to compensate for dietary deficiencies and to ameliorate their disease. Efficacy appeared less important to users than safety. CAM practitioners were regarded as more convincing, informative, considerate and available compared with mainstream health professionals.Conclusions: Communication between patients and mainstream health professionals about CAM use could be improved by health professionals being more accepting of CAM use and having some basic knowledge about commonly used CAM preparations.

Johnson George MPharm · David C M Kong MPharm PhD · Kay Stewart BPharm(Hons), PhD · Lisa L Ioannides-Demos BPharm, PhD · Nick M Santamaria RN, PhD

Some knowledge of complementary and alternative medicine is essential if we are to support patients in making healthcare choices Complementary medicine use is increasing in Australia and other developed countries, with nearly 50% of Australians taking a complementary therapy in any one year and an increasing number of doctors prescribing these forms of treatment.1 With this widespread use, it seems rational for the medical practitioners of tomorrow to be provided with some knowledge of complementary therapies, particularly from an evidence-based perspective.2 There is also significant interest from students and recent graduates in training in this topic.3 The article by Owen and Lewith in this issue of the Journal (page 276) outlines experience in CAM teaching within one of the newer medical schools in the United Kingdom (Southampton).4 It points out that CAM familiarisation courses are relatively new, but do provide students with a knowledge of complementary therapies and the ability to discuss these with their patients. The use of specific learning objectives provides a rational approach to learning and gives students a benchmark for what they need to know. It would seem that the teaching of CAM familiarisation in Australian medical schools is still varied. A recent review conducted specifically for this series suggests that there are few dedicated CAM familiarisation courses in Australian medical schools (Associate Professor Alan Bensoussan, Director, Centre for Complementary Medicine Research, University of Western Sydney, personal communication). Some Australian medical schools are in the process of revising their curricula, with several considering the addition of a CAM component. CAM may be taught as an independent elective, within another unit such as “society, health and health psychology”, or in the teaching of ethics. Major training programs for complementary medicine practitioners in Australia are run by universities which do not have medical schools, so expertise in CAM usually has to be brought into the medical schools from outside their universities. The Australian Medical Council (AMC) produced a position statement, endorsed in July 2000, which reviewed the status of CAM courses in Australia.5 It reported that at least 16 degree courses in “unorthodox” practices were offered at a university level, in addition to courses at colleges of technical and further education and through independent training providers. It is unfortunate that, in the title of the position statement, the term “unorthodox” was used rather than the more commonly accepted term “complementary”. The position statement actually goes to great lengths to justify its use of this word, saying that it is non-mainstream health practices that should be referred to as “unorthodox”. Given that “mainstream,” according to the , refers to “the prevailing trend of opinion, fashion, etc”, the fact that over 50% of the population use alternative treatments suggests that the AMC has taken the viewpoint of the profession rather than the patient. Not surprising, perhaps, but we should remember that the healthcare system is supposed to work for patients as well as doctors. The AMC document does, however, provide a list of objectives relating to knowledge and understanding of complementary therapies and encourages medical schools to devise teaching and learning strategies that address these.5 It points out that “unorthodox practices that can be demonstrated by the methodology of evidence-based medicine to be efficacious become orthodox by definition, even if the scientific basis of their efficacy is not understood”, and that medical graduates “need to have some knowledge of the range of unorthodox practices, the needs they meet, their effectiveness and safety, the extent of their use and their costs”.5 It also points out that Medical Board “guidelines” encourage doctors to present all the information available to allow patients to make informed choices about their management. In terms of skills that should be gained by medical students, the position paper focuses on the importance of history taking, which should include any use of complementary therapies. It should be appreciated that the Cochrane electronic library currently houses more than 80 CAM-related full-text systematic reviews and about 5000 CAM-related clinical trials and that these should be used as a teaching resource.6 Of singular importance in teaching students about CAM is that they are given a broad view of the strengths and weaknesses of CAM therapies, and how to assess their efficacy. These principles are no different to those of the approach to medicine in general. Practitioners of today and tomorrow must appreciate that patients may choose to use CAM therapies and that we are there to assist them in making those choices.

Peter M Brooks MD, FRACP

As the use of CAM grows, CAM familiarisation offers educational opportunities for undergraduates to understand CAM, their attitudes to medical change and the process of evidence-based medicine. Such courses also offer the opportunity to integrate patient care and improve the relationship between medical and CAM practitioners. CAM familiarisation courses are available in many medical schools in the United States and the United Kingdom. The multiprofessional model which we have developed at the University of Southampton (UK) offers valuable experience to those thinking of establishing such courses.

David Owen MRCS, LRCP, FFHOM · George T Lewith DM, FRCP

Most consumers consider complementary and alternative medicine (CAM) products inherently safe. The growing simultaneous use of CAM products and pharmaceutical drugs by Australian consumers increases the risk of CAM–drug interactions. The Therapeutic Goods Administration (TGA) has a two-tier, risk-based regulatory system for therapeutic goods — CAM products are regulated as low risk products and are assessed for quality and safety; and sponsors of products must hold the evidence for any claim of efficacy made about them. Adverse reactions to CAM products can be classified as intrinsic (innate to the product), or extrinsic (where the risk is not related to the product itself, but results from the failure of good manufacturing practice). Adverse reactions to CAM practices can be classified as risks of commission (which includes removal of medical therapy) and risks of omission (which includes failure to refer when appropriate). While few systematic studies of adverse events with CAM exist, and under-reporting is likely, most CAM products and practices do not appear to present a high risk; their safety needs to be put into the perspective of wider safety issues. A priority for research is to rigorously define the risks associated with both CAM products and practices so that their potential impact on public health can be assessed.

Stephen P Myers PhD, BMed, ND · Phillip A Cheras PhD, BAppSc

Integrated clinics have already been established in response to community demand. The growing evidence base for complementary and alternative medicine (CAM) and its widespread community use compels doctors to understand complementary therapies and to refer patients to CAM practitioners where appropriate. Most general practitioners have patients with chronic illness who could benefit from the services of CAM practitioners, and virtually all CAM practitioners have patients who require access to mainstream diagnosis and therapy. Collaboration requires shared respect and trust, and education. Dangers of not integrating care include delaying or depriving patients of safe and effective management, and the potential for harmful interactions. Integration is currently being supported by government initiatives such as the new MedicarePlus package, as well as by initiatives from organisations such as the Australian Medical Association, the Royal Australian College of General Practitioners and the Australasian Integrative Medicine Association.

Marc M Cohen MB BS(Hons), PhD, BMedSc(Hons)

A complementary and alternative medicine (CAM) system divorced from scientific medicine means that patients can only benefit from the best of both systems by dividing their care. Science must be used to stimulate convergence of complementary and traditional healthcare. First class research to examine the more interesting claims of the alternative health industry is essential to broaden the range of therapeutic options available, while minimising fraudulent, ill-informed and sometimes dangerous practices. Mutual respect and interest between orthodox and alternative practitioners is appropriate, but there can be no compromise involving unscientific approaches to care. Health departments must play a greater role in stopping fraudulent claims being publicised, and in warning consumers about such claims.

John M Dwyer AO, FRACP, PhD

Understanding change in the 21st century will help us in the CAM debate Medical revolutions are often led by unique biological discoveries, like penicillin, or by technical advances, like microsurgery. Evidence-based medicine (EBM) is a more recent example of a movement led by clinicians seeking greater certainty in outcomes for patients; the Human Genome Project is a movement led by benchtop scientists driven by the vision for more tailored and effective medicines. Not so with complementary and alternative medicine (CAM), where the patient heads the revolution, in the vanguard of an apparently insatiable demand for therapies that may vary from the acceptable face of acupuncture to the more extraordinary claims of crystal therapy. In Australia, each year, we spend more on CAM products than our out-of-pocket contributions to pharmaceuticals.1 In the United States, there are now more CAM consultations than conventional consultations in primary care, while demand for and expenditure on CAM has doubled over the decade of the 1990s.2 A similar situation exists in the United Kingdom.3 In this issue of the Journal we begin a special series on CAM. Rather than dissecting its various diagnostic and therapeutic modalities, the series aims to take a look behind the scenes at CAM’s place in healthcare, in our ethical and legal frameworks and in society generally. We hope to initiate proper debate on CAM, and to promote better understanding of its current and potential roles in healthcare. Coulter and Willis (page 587) start this series with a comprehensive review of the background to the growth of CAM, and propose that the reasons for this growth relate to general societal changes rather than intrinsic concerns with medicine.4 They argue that this change within society might be interpreted as part of the ascendancy of patient self-empowerment, and describe approaches that conventional medicine can take to respond to this growth. It is strange that, at a time when we can do so much more with conventional medicine than we could 50 years ago, increasing numbers of individuals seek CAM for illnesses (such as asthma) which can be effectively and safely managed with conventional approaches. This can place doctors in a very difficult position. What do they do when confronted with a patient who seems to know more about herbal medicine or acupuncture than they do? How do they assess and evaluate an article that claims herbal medicine is effective in the management of inflammatory bowel disease, and to whom do they refer? How should we counsel our graduates to manage these demands, and how should we prepare them for a process of lifelong learning with respect to CAM? These are issues not generally dealt with in most Australian medical schools, and which will be tackled in the series. The emphasis on EBM has at its foundation a desire for improved patient safety, appropriate healthcare expenditure and better disease management. While it is no longer appropriate to dismiss CAM as an evidence-free zone, nor to dismiss educated consumers as misguided individuals, an accelerated research effort remains essential to determine clearly the effectiveness and safety of many CAM products and services. The high (and growing) levels of CAM use indicate that patients, at least, perceive that CAM interventions are effective. Among the issues that will form the focus of debate in the series are questions like: Do many conventional physicians assume patients seek CAM because they believe it to be a more, or equally, effective treatment? On what basis should we integrate CAM into conventional medical care and do we need evidence before integration? Are we, as physicians, medicalising the CAM model when perhaps our patients are trying to escape that model through their use of a particular mind–body therapy? These issues reflect directly on conventional healthcare delivery and the therapeutic relationship between doctor and patient. Almost all doctors in clinical practice will at some point “share care” with a complementary medicine practitioner. This may, of course, not be disclosed to them by their patients! However, if a doctor refers patients to a CAM practitioner, or vice versa, what is the professional relationship and what are the legal and ethical considerations within that relationship? Above all else, we have a duty of care to our patients — “primum non nocere”. With this in mind, it is essential that we establish the professional competence and safety of CAM practitioners and the products they prescribe. The following terms have been variously applied to the relationship between CAM and conventional medicine: Pluralism — a positive outcome of multiculturalism, attempts to encourage mutual respect for contrasting systems; Harmonisation — the diplomatic approach of the World Health Organization, where conventional and traditional (indigenous) medicines work together with no predetermined outcomes or biases; and Integration — the selective incorporation of elements of CAM and conventional medicine. However, true integration will only be possible if CAM commits to appropriate scientific scrutiny and if treatment guidelines are developed that clearly dictate when one option should be selected over (or alongside) another (based on effectiveness, safety, cost, convenience, etc). CAM raises a number of very important issues for medical practice, not least the sanctity, integrity and power of the therapeutic relationship. As our patients become more educated, vocal and vociferous, the medical profession can no longer just be the “possessor of knowledge” but must also provide interpretation and wise counsel. The debates around CAM bring this to the fore and highlight the need for more research, not only on efficacy, but also the cultural and political changes demanded of medicine in the 21st century. The sooner we can understand and manage the change, the more comfortable our role will be as caring physicians. Yet the growth in the use of CAM may have outpaced the development of government policy and the capacity for healthcare professions, insurers and industry to manage emerging issues effectively. It is therefore essential that we sustain, support and develop a coherent research strategy for CAM, and this series will generate suggestions as to how this might be best developed within an Australian context. Medical science holds no unique handle on truth. Much of what is taught now will be unlikely to be practised in 20 years’ time, bearing in mind recent examples such as changes in the evidence for use of HRT (in pharmacotherapy). We hope you enjoy the series, and we look forward to reader participation in the discussion and debate of the issues it raises.

George T Lewith DM, FRCP · Alan Bensoussan PhD

Major reasons for the growth in the use of complementary and alternative medicine (CAM), in Australia and elsewhere, are general societal changes rather than specific reasons internal to medicine. There are problems of definition of CAM, as well as the extent to which CAM modalities can be considered a unified paradigm. The general changes examined include the consumer and green movements, as well as postmodernism. The movement surrounding evidence-based healthcare may provide some answers, but will not settle the issue of compatibility. CAM is here to stay and will continue to present challenges for conventional medicine on how to respond.

Ian D Coulter PhD · Evan M Willis PhD

Michael Thomsen,* Luis Vitetta,† Avni Sali,‡ Matthias Schmidt§ * Research Associate, † Deputy Head, and Director of Research, ‡ Head, Graduate School of Integrative Medicine, Swinburne University, 9 Frederick Street, Hawthorn, VIC 3122; § Research Head of Toxicology, Society of Nutritional Medicine and Dietetics, Harsewinkel, Germany. LVitettaATmedicine.swin.edu.au To the Editor: We wish to comment on the case report by Lontos and colleagues on the proposed causal relationship between the herb black cohosh (Cimicifuga racemosa) and acute hepatic failure.1 One other case has been reported in Australia,2 and the evidence linking black cohosh to liver toxicity was weak and contested.3 The medication in the case report presented by Lontos and colleagues1 included a herb (ground ivy) containing a known liver toxin (pulegone). Pulegone is considered a strong hepatotoxin and should not be dismissed, even though it was reported that there was less pulegone in ground ivy than in pennyroyal. The authors do not indicate the daily dose of the pulegone ingested. The Therapeutic Goods Administration (TGA) made only qualitative analyses of three of the five herbs in the mixture. In our opinion the most suspect ingredient was ground ivy, and it was not assayed. The argument that the TGA could not find a standard for pulegone or ground ivy is untenable given the level of expertise and the capacity of the TGA and its laboratories. Was the supply company asked to provide analytical evidence of the contents of the herbal extracts? Ground ivy is not known to be hepatotoxic, but it is possible that the extract could have contained ground ivy with pennyroyal, which might explain the hepatoxicity of the mixture. Although uncertain without thoroughly investigating all ingredients in the herbal mixture, this alternative is a possibility. Without thorough investigation of herbal preparations, adverse events attributed to certain herbs remain dubious at best. Black cohosh has a very good safety record. There is a large body of clinical evidence and research which suggests that this herb has no hepatotoxic effects. Indeed, a German manufacturer has sold more than 350 million daily doses of black cohosh preparations worldwide since the pharmacovigilance system was introduced, and no comparable cases have been reported until these two reports in Australia. An Ames test (salmonella microsomal assay) showed no in-vitro evidence of mutagenic potential of an extract of black cohosh,4 and no chemical or organ toxicities were observed in Wistar rats given up to 5000 mg of a Cimicifuga racemosa extract granulate per kilogram body weight for 26 weeks.5 What may also be of concern is that the TGA may not have the full capabilities to test ingredients used in Australian herbal products. That substitution of herbs with potentially toxic herbs may be a common event, and that neither the TGA nor the manufacturers may have the expertise to prevent deleterious contaminants, is of even greater concern.

Michael Thomsen · Luis Vitetta · Avni Sali · Matthias Schmidt

Fiona J Cumming,* Larry Kelly† * Director, Office of Complementary Medicines; † Acting Director, TGA Laboratories; Therapeutic Goods Administration, PO Box 100, Woden, ACT 2606. fiona.cummingAThealth.gov.au Comment: Thomsen and colleagues have pointed to what they believe were uncertainties in the case described by Lontos et al, associating the use of a herbal preparation containing black cohosh with acute liver failure.1 They assert that on the basis of these uncertainties, and other evidence, black cohosh was unlikely to have been the cause of the liver failure. There are indeed uncertainties about the cause of the illness. The first, and quite critical one, is that we cannot be certain that the patient was given the same herbal materials as those supplied to the Therapeutic Goods Administration (TGA) for analysis. The pharmacist who dispensed the herbal formula for the patient provided the TGA with samples for analysis of each of the five individual extracts in the formula. Documentary evidence supporting the correct identity of the five herbs was supplied in the form of certificates of analysis from the manufacturers of the individual herbal extracts. However, it was not possible to ascertain whether the exact batch of the exact formulation taken by the patient was that which was tested by the TGA. While the title of the article by Lontos et al suggests a “problem” with black cohosh, the body of the article makes clear that the causative agent(s) are unknown,1 which is in agreement with the letter by Thomsen et al.1 Thomsen and colleagues claim that the TGA did not test the ground ivy extract supplied by Lontos et al, and said that this was because the TGA did not have a standard for pulegone or ground ivy. This is not the case, and the letter by Lontos et al1 does not state that either. The reason the TGA did not test initially for pulegone was because it is a minor constituent of the essential oil of ground ivy. We did not expect there to be any significant levels of this compound. In fact, we have subsequently confirmed that pulegone was not detectable (limit of detection 5 ppm) in the sample of ground ivy extract provided by Lontos et al. Thomsen and colleagues refer to the good safety record of black cohosh in Australia and internationally, and claim there has been only one other case in Australia where black cohosh was linked to liver toxicity. Some caution is needed in drawing broad conclusions about the safety of herbal medicines. Most countries do not have adverse reaction reporting systems which include herbal remedies. In Australia, where we have a well-developed reporting system, there have been several reports of liver problems in patients taking various preparations containing black cohosh. However, causality has not been established beyond doubt in these cases. The TGA has state-of-the-art testing facilities and a team of internationally recognised scientific staff. The formulation supplied to the patient was extemporaneously dispensed by a pharmacist. Such medicines are not subject to the regulatory controls of the TGA and would not normally be included in the TGA’s testing program. However, the TGA offered to test the herbal formulation supplied by the pharmacist to assist the clinical team. The results of the TGA’s testing confirmed the absence of undeclared pharmaceuticals in the samples of herbal extracts provided. In view of these uncertainties, it is not possible to conclusively identify the cause of the patient’s liver failure. On the evidence available it cannot be concluded that black cohosh was a cause. It is simply not possible to rule in or rule out black cohosh, or indeed any of the other herbal extracts in the formulation taken by the patient, as a cause. Where practitioners suspect a complementary medicine is involved in an adverse reaction, providing the exact product and batch taken by the patient is essential if laboratory testing is to help in confirming causality.

Fiona J Cumming · Larry Kelly

Michael Thomsen,* Luis Vitetta,† Mathias Schmidt,‡ Avni Sali§ * Research Associate, † Director of Research, § Head, Graduate School of Integrative Medicine, Swinburne University, 9 Frederick Street, Hawthorne, VIC 3122; ‡ Head of Toxicology, Society of Nutritional Medicine and Dietetics, Harsewinkel, Germany. lvitettaATmedicine.swin.edu.au To the Editor: Gow and colleagues recently attributed fulminant hepatic failure in an Australian patient to an over-the-counter herbal product containing kava (Piper methysticum) that is extensively used in the community.1 We are not convinced that kava caused this patient’s liver failure. The hepatotoxicity could have been due to other unidentified contaminants of the herbal preparation or to chromium (from the mineral supplements also taken by the patient). We tested a sample of the product Kava 1800 Plus (Eagle Pharmaceuticals, Batch No. 10711) by thin layer chromatography (TLC) and high pressure liquid chromatography (HPLC) methods, and assessed it against defined standards. Kavalactones were identified and quantified by normal-phase HPLC. Kava was positively identified, with a content of about 47 mg of kavalactones per tablet (the product label specifies 60 mg per tablet). However, flavonoids from Scutellaria lateriflora, analysed by reverse-phase HPLC, could not be found. Passiflora incarnata, analysed by TLC, was also not found, with none of the typical flavonoid bands being detectable. The absence of two ingredients listed on the product label, P. incarnata and S. lateriflora, raises a new concern that there may be batch variations, as well as the possibility of unknown adulterants or contaminants being present. The possibilities of contaminants and batch variation were not excluded in the case report by Gow and colleagues.1 The Therapeutic Goods Administration established that Kava 1800 Plus did not contain common germander (Teucrium chaemaedrys), a known adulterant for S. lateriflora. However, Teucrium species are known to have hepatotoxic effects and there are about 100 species, any one of which could have been a contaminant. Gow et al refer to 68 international case reports of suspected hepatotoxicity with the use of kava.1 An independent analysis of these 68 cases concluded that only two were probable kava-associated hepatotoxicities.2 An incidence calculation from these case reports indicates that hepatotoxicity from kava occurs in 0.008 cases per million daily doses,2 which represents an extremely low risk of adverse reactions associated with kava. Recently, a study on the potential hepatotoxicity of kava found that the aqueous extract of kava does not affect results of liver function tests in rats. Extracts were administered in daily dosages of 200 or 500 mg of active kavalactones per kilogram of bodyweight for 2 or 4 weeks. Sera were assayed for four enzymes that are markers of liver toxicity, and liver homogenates were assayed for malondialdehyde formation, which indicates changes in lipid peroxidation. Kava did not elevate malondialdehyde or the enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase or lactate dehydrogenase. In fact, in certain instances, these enzymes were significantly reduced, suggesting a lack of toxic effect of kava on the liver.3 TLC analyses have shown that there is no qualitative difference between aqueous, acetone or ethanol extracts of kava.4 We propose, given that patients can consume other over-the-counter products such as chromium (shown to have hepatotoxicity at high concentrations),5 that all products consumed by patients must be evaluated before causality can be attributed to a particular herb. Reports of case records associated with hepatic failure due to kava require proper verification and documentation of all the findings.

Michael Thomsen · Luis Vitetta · Mathias Schmidt · Avni Sali

Paul J Gow,* Nathan J Connelly,† Richard L Hill,‡ Peter Crowley,§ Peter W Angus¶ * Gastroenterologist, † Gastroenterology Registrar, ¶ Director, Department of Gastroenterology and Liver Transplantation, § Pathologist, Department of Anatomical Pathology, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, VIC 3084; ‡ Medical Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Canberra. paul.gowATarmc.org.au In reply: Thomsen et al raise several points regarding our recent report of a death following ingestion of a preparation containing kava.1 The first is that the results of their analysis of the herbal preparation differ from those of the Therapeutic Goods Administration (TGA). The TGA found Passiflora incarnata in the tablets, whereas Thomsen and colleagues did not. The explanation for this lies in the fact that different batches of the product were analysed by the two laboratories. The analysis we reported relates to batch 13861, which was the source of the patient’s tablets. Thomsen and colleagues have analysed material from a different batch that may have contained different components. Thomsen et al also raise the possibility that Teucrium, a known adulterant of Scutellaria, may have been present in the preparation. With respect to this issue, the TGA tested for both T. chamaedrys and T. canadensis and found none present. They also tested for the presence of the chemicals teucreoside and verbascoside, both of which are found in many Teucrium species. Neither was present. The raw materials used to make the tablets were also analysed, and no evidence of Teucrium substitution or contamination could be found. The next point raised is whether the association between kava use and hepatotoxicity is causal, and they quote an analysis published in the journal Phytomedicine, in which the authors claimed that kava was the probable cause in only two of 68 reviewed cases. In marked contrast, the Journal of Hepatology, in July 2003, published an analysis of 36 cases of hepatitis associated with the use of kava.2 The review concluded that kava was the certain or probable cause of the hepatitis in 24 of the 36 cases. Worryingly, eight of these patients required liver transplantation. Thomsen and colleagues then point to a lack of evidence of hepatotoxicity in studies in rats administered kavalactones.3 We believe it is inappropriate and misleading to suggest that a study of this kind could rule out the possibility that kava preparations cause life-threatening but uncommon idiosyncratic hepatotoxic reactions in humans. Finally, Thomsen et al wonder whether the patient’s illness may have been due to chromium toxicity. However, the illness was not suggestive of chromium poisoning.4 There is no reason to believe that chromium was present at other than normal background levels.

Paul J Gow · Nathan J Connelly · Richard L Hill · Peter Crowley · Peter W Angus

R Frank Gorman Medical Ophthalmologist, PO Box 211 Marrickville, NSW, 1475. rfgormanAThotmail.com To the Editor: Ernst raises the matter of obstacles to research in complementary and alternative medicine. With respect to spinal manipulation therapy as an alternative medical approach to constitutional ailments, such as migraine, the key evidence is the recovery of vision, which occurs with spinal manipulation in appropriately ill patients. These data have not been acknowledged by this Journal because randomised controlled trials have not been performed. Ernst says, “Randomisation is only ethical if there is substantial uncertainty about the best treatment for that patient.”1 Applied to the recovery of vision with spinal manipulation, this ethical principle prevents any randomised trials from being performed in studying that phenomenon. In 1992, I sent 12 consecutive patients demonstrating constricted visual fields to four senior fellows of the then Royal Australian College of Ophthalmologists. The patients were examined by those consultant scrutineers, who agreed that the visual fields were constricted in all occasions. The patients were seen at independent locations, and I was present only on one occasion. The patients were then treated by spinal manipulation under anaesthesia, with immediate recovery of the visual fields being noted on wakening from anaesthesia.2 This recovery of vision merely reiterated many earlier anecdotal demonstrations.3-5 In every case, the scrutineers agreed that the vision had recovered when, at an independent location subsequent to the treatment, they saw the patients. Further, when Stephens and his associates, including me, treated 17 patients by outpatient chiropractic spinal adjustments, that entire group showed immediate improvement in the visual fields, as measured by computerised static perimetry.6 Sletteberg and his associates found that 55% of patients with constricted visual fields of the type under discussion still had the visual disability on re-examination on a mean review period of 7 years after orthodox treatment.7 Kathol and his associates also found that 55% of these patients still had the visual disability at a mean review period of 4 years.8 When the 100 per cent improvement obtained by spinal manipulation is compared with results of orthodox medical treatment (45% improvement at mean review periods of 7 and 4 years), it is clear that spinal manipulation is more effective than orthodox medical treatment, so much so that to repeat the experiment would be unethical. In my personal experience, the main obstacle to research of complementary medicine precepts has been the censorship of dissenting data from orthodox medical literature. The most blatant example of this is the studied neglect of the “tunnel vision information”: the knowledge that vision improves in appropriately ill patients when the spine is manipulated.

R Frank Gorman

Edzard Ernst Director, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, UK. Edzard. ErnstATpms.ac.uk In reply: Gorman’s story is characteristic of complementary/alternative medicine (CAM): someone makes an observation inconsistent with current medical teaching, and subsequently becomes convinced that therapy X is “100 per cent” effective. Yet clinical trials are never conducted and therapy X assumes somewhat of a cult status. Its proponents name various reasons why clinical trials are unavailable. In some instances (not in the case of spinal manipulation for recovery of vision), clinical trials do eventually emerge. These show that therapy X does not work. Proponents view this as a confirmation of their conspiracy theory. Eventually the cult status of therapy X becomes established. This dangerous scenario would be avoidable if CAM proponents understood the role of science in testing emerging treatments. It is, of course, not unethical to conduct a randomised trial on spinal manipulation for recovery of vision. Sure, randomisation is only ethical if there is uncertainty, but to deny that uncertainty exists is unreasonable — as is the notion of “censorship of dissenting data from orthodox medical” journals. Gorman’s reference list shows that even CAM journals have resisted publishing the effects of spinal manipulation on vision recovery. My conclusion is simple: science and medical publishing follow certain rules for good reasons. CAM should learn to follow them.

Edzard Ernst

Vivian Lin President, Chinese Medicine Registration Board of Victoria, PO Box 5088, Alphington, VIC 3078. adminATcmrb.vic.gov.au To the Editor: The Chinese Medicine Registration Board of Victoria would like to provide updated information relevant to the debate on the article by Parker.1 All practitioners of acupuncture and Chinese herbal medicine in Victoria are now legally required to register. The Chinese Medicine Registration Act 2000 (Vic) specifically includes transitional arrangements, and the Board has developed a “grandparenting policy” for assessing registration applications until 31 December 2004. There are six key assessment areas for all applicants: adequacy of qualification (minimum requirements); recency of practice; competence; good character; fitness to practise; and having the required professional indemnity insurance, first aid and effective communication arrangements. Details are available at www.cmrb.vic.gov.au. To date, 740 practitioners have become registered, and 11.5% of applicants have had a registration refusal or conditions imposed. After the grandparenting period, new applicants will be required to complete an approved course or pass an examination set by the Board. The Board will consider advanced diploma courses for approval up until December 2007, after which the minimum level will be a bachelor degree. Complaints are handled according to the Act, which is modelled on the medical (and other health) practice Acts. The current Victorian model dictates that the Board include two non-practitioners, one legally qualified member and six practitioners with a minimum of 5 years practice experience. Very specific steps must be taken in dealing with complaints, and 28 complaints have already been investigated. The issues of concern include infection control, advertising, professional ethics and communication with patients. Other boards (not medical practitioners) have asked us to assist with endorsement of their registrants, mainly for acupuncture. The Medical Practitioners Board of Victoria plans to ask medical practitioners seeking endorsement for Chinese herbal medicine to register directly with us. We hope this information will help contribute to informed debate on the regulation of complementary and alternative medicine.

Vivian Lin

Steve Lontos,* Robert M Jones,† Peter W Angus,‡ Paul J Gow§ * Liver Transplant Registrar, † Director, Liver Transplant Unit, ‡ Director, Department of Gastroenterology, § Gastroenterologist, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, VIC 3084 paul.gowATarmc.org.au To the Editor: We wish to report a case of acute liver failure associated with the use of a herbal preparation that contained several ingredients, including Cimicifuga racemosa (black cohosh). In January 2003, a 52-year-old woman was referred to our unit with acute liver failure. She had taken a herbal preparation for three months (for severe tinnitus), but ceased four weeks before admission. The preparation was made and provided by a pharmacist. The preparation was supplied in a 200 mL bottle and contained a mixture of the fluid extracts of Nepeta hederacea (ground ivy) 80 mL, Hydrastis canadensis (golden seal) 20 mL, Ginkgo biloba (ginkgo) 40 mL, Avena sativa (oats seed) 40 mL and Cimicifuga racemosa (black cohosh) 20 mL. According to the information supplied by the pharmacist, one gram of herb was contained in each 1 mL of extract, with the exception of golden seal, for which 0.5 g of herb was contained in each millilitre. The oats seed fluid extract was supplied by Southern Cross Herbal School (Gosford, NSW), and all other fluid extracts were supplied by the Herbal Extract Company of Australia (Sydney, NSW). The patient took a total of 600 mL over the 3-month period (7.5 mL bd orally as required). Before developing symptoms of liver failure, the patient had taken no other medications and had no risk factors for the acquisition of viral hepatitis. On arrival, she was deeply jaundiced but not encephalopathic. Liver span was reduced and there were no signs of chronic liver disease. The international normalised ratio was 3.0 (normal, 1.0–1.2), and she had serum concentrations of albumin, 26 g/L (normal, 35–50 g/L); bilirubin, 368 μmol/L (normal, < 18 μmol/L); alkaline phosphatase, 230 U/L (normal, 35–104 U/L); alanine aminotransferase, 1380 U/L (normal, < 55 U/L); and g glutamyl-transpeptidase, 134 U/L (normal, < 45 U/L). Extensive investigation excluded other recognised causes of acute liver failure. Her condition deteriorated over the following week, with the development of hepatic encephalopathy and hepatorenal failure. She underwent liver transplantation in early February 2003, and had an uneventful postoperative course. Examination of the explanted liver revealed massive hepatic necrosis. Following transplantation, the pharmacist supplied samples of the individual extracts to the Therapeutic Goods Administration (Canberra) for analysis. The analysis revealed no undeclared pharmaceutical drugs. Assay of the individual extracts of golden seal, ginkgo and black cohosh revealed the listed ingredients to be present. The presence of ground ivy and oats seed in the extracts has not yet been confirmed owing to the lack of a suitable reference standard. It is not possible to determine the individual ingredient, or mixture of ingredients, that resulted in acute liver failure in this patient. However, this is the third case of acute liver failure associated with black cohosh ingestion to be reported recently in Australia.1 In this instance, liver failure progressed despite cessation of the herbal therapy, and transplantation was required, suggesting that a process of irreversible liver injury had been initiated before treatment was ceased. It should be noted that ground ivy contains pulegone, a known hepatotoxin. However, the concentration of pulegone in ground ivy is accepted to be vastly less than in pennyroyal, where pulegone-induced hepatotoxicity has been reported.2 To our knowledge, there are no reports of golden seal, oats seed or ginkgo causing hepatotoxicity. The popularity of herbal therapies is due in part to their perceived lack of side effects. It is important for the medical and broader community to be aware of the potential toxicity of these preparations. In any patient presenting with unexplained hepatitis it is essential to determine if there has been exposure to herbal therapies, since early cessation of treatment may be life saving.

Steve Lontos · Robert M Jones · Peter W Angus · Paul J Gow

If we address the obstacles, high quality CAM research is possible About half the general population in developed countries uses complementary and alternative medicine (CAM).1 Yet many conventional healthcare professionals refuse to take CAM seriously — one often-voiced argument is “there is no research in CAM”.2 Certainly, for some modalities there is no compelling evidence base,3 and some of the research into CAM has methodological flaws and biases.4,5 On the other hand, many doctors and medical educators are uninformed about the quality evidence that does exist.6 In this article, I discuss some of the obstacles to developing an evidence base for CAM. Financial obstaclesIn most countries, CAM research funding is on a very small scale. For instance, only 0.08% of the British National Health Service research budget goes towards CAM research.7 Even though recent initiatives in the United Kingdom, United States and Australia have specifically freed up funds for CAM research, these amounts are minute compared with funding in other areas of medicine. It is likely that lack of plausibility of many CAM therapies deters scientific review committees from defining CAM as a priority. A vicious circle may ensue: little plausibility means no funds, therefore no preliminary research, therefore little plausibility. Clinical trials of CAM can be even more expensive than those of conventional medicine. CAM treatments are often therapist-led, effect sizes are often small (requiring large sample sizes), and therapeutic effects may appear only after long treatment periods, all of which mean greater expense. For most CAM modalities, intellectual property cannot be protected; thus commercial investments are rarely forthcoming. This shortage of CAM research funds has three important consequences: it prevents relevant projects from happening; it hinders the development of a research infrastructure similar to that of conventional medicine; and it keeps well-trained career scientists from entering into the field. Methodological obstaclesMany CAM therapies (eg, massage therapy) are physical by nature, which creates methodological challenges. What, for instance, is an acceptable “placebo” control for a trial of massage treatments? Like several other areas of conventional medicine (eg, physiotherapy, surgery, psychotherapy), blinding patients in clinical trials can be difficult or even impossible. Thus the highest level of scientific rigour can be barred to trials of CAM. Many CAM researchers also believe that their holistic approach can not be readily put into the “straitjacket” of a randomised controlled trial (RCT).8 This argument is demonstrably wrong, and its persistence in CAM circles continues to impede efficacy research. One can, of course, conduct an RCT comparing a complex, individualised, “holistic” treatment package to the standard care for that condition. This may require some innovative adaptations to the standard design, but, in principle, RCTs are usually feasible.9 For many people, CAM is an emotive subject. As a result, patients may not want to take a chance with randomisation, and many CAM practitioners may oppose scientific evaluation of their treatments, further hindering clinical trials. There is more to most CAM interventions than meets the eye. For instance, some are based on theories that fly in the face of science. Researchers might conduct a clinical trial of traditional acupuncture, spiritual healing or homoeopathy and see this as a relatively straightforward exercise. Proponents of these therapies may, however, view it as a test of some ancient theories of life forces, spiritual energies or ultramolecular phenomena. Such discrepancies can (and usually do) create unforeseeable methodological problems, as well as obstacles for research and interpretation of results. Ethical obstaclesIt is an important ethical requirement for randomised clinical trials that the investigators be in the state of equipoise (ie, they must believe that the test intervention is at least as good as the control intervention or placebo). If this is not the case (as for many CAM researchers), it is, strictly speaking, unethical for investigators to conduct the study. “Randomisation is only ethical if there is substantial uncertainty about the best treatment for that patient”.10 A further important ethical requirement for clinical research is informed consent from patients or healthy volunteers.11 As mentioned above, this may be difficult or impossible to obtain in an environment where patients’ enthusiasm often is strongly in favour of CAM and against receiving a control (placebo or non-CAM) treatment. Such problems constitute further impediments to good CAM research. ConclusionAlthough high quality CAM research does exist,3 many projects have, in the past, been less rigorous than they could have been. Before we condemn CAM for this situation, we should ask what the obstacles to CAM research are. Removing these obstacles will require dedicating adequate funds to CAM research, attracting career scientists into the field, adequately addressing the complexity of CAM and minimising bias with carefully designed studies.

Edzard Ernst MD, PhD, FRCP

Objectives: To compare the characteristics of complementary and alternative medicine (CAM) users and non-users among Australian women.Design: Cross-sectional postal questionnaire conducted during 1996, forming the baseline survey of the Australian Longitudinal Study on Women’s Health.Participants: Women aged 18–23 years (n = 14 779), 45–50 years (n = 14 099) and 70–75 years (n = 12 939), randomly selected from the Health Insurance Commission database, with over-sampling of women from rural and remote areas of Australia.Main outcome measures: Consultation with an alternative health practitioner in the 12 months before the survey.Results: Women in the mid-age cohort were more likely to have consulted an alternative health practitioner in the previous year (28%) than women in the younger cohort (19%) or older cohort (15%). In all age groups, CAM users were more likely than CAM non-users to reside in non-urban areas, to report poorer health, have more symptoms and illness, and be higher users of conventional health services.Conclusions: Women in non-urban Australia are more likely to use CAM but do so in in parallel with conventional health services.

Jon Adams PhD · David W Sibbritt PhD · Gary Easthope PhD · Anne F Young PhD

In response to the increasing use of complementary and alternative medicine (CAM), governments are exploring ways to ensure patients’ safety and respond to complaints. One solution is to establish registration boards and procedures based on the model of existing health practitioner Acts. Registration will require defined minimum standards for competence, which will have to be based on scientific evidence. As scientific evidence accumulates, these modalities are likely to lose their identities as “alternative” and become assimilated into Western medicine.

Malcolm H Parker MB BS, MLitt

Some complementary health modalities have found a well-accepted place in palliative care. The interdisciplinary nature of palliative care underlies the common acceptance of complementary therapies in this field of care. The experience of the interdisciplinary approach in palliative care may presage current changes in attitude towards complementary therapies in other areas of medicine. Growing collegiality and interdisciplinary teamwork in healthcare is encouraging the medical profession to see beyond scientific reservations and view complementary modalities as providing supportive roles.

Allan Kellehear PhD

Differences in kava extraction methods may affect hepatotoxicity In this issue of the Journal, Gow and colleagues (page 442) report the first Australian case of fulminant hepatic failure attributed to a herbal product containing kava,1 while Moulds and Malani (page 451) note the cultural and economic importance of kava for Pacific island nations, and provide a balanced overview on kava safety and availability.2 For centuries kava has been widely consumed in Pacific island countries as a ceremonial beverage and for its mood-altering and stress-relieving properties. It is prepared as an aqueous emulsion of the crushed fresh or dried roots or lower stems of the kava shrub Piper methysticum ("intoxicating pepper").3 Pharmacological properties, such as anxiolytic activity, are attributed to a poorly characterised group of compounds termed kavalactones.3,4 In 1982, kava was introduced to some Arnhem Land Aboriginal communities from Pacific island countries, in part to reduce the harmful effects of alcohol.5 Kava use continued to rise during the 1980s and 1990s, supplied by a lucrative black market. Concerns about adverse health, social and economic effects of widespread heavy consumption resulted in the Northern Territory Kava Management Act in May 1998, which made the possession of more than 2 kg of kava illegal unless in accordance with a licence. However, an illegal trade continued, with profiteering by those distributing kava imported from several Pacific island countries. In October 2000, the Kava Management Act was amended to incorporate harm reduction objectives and a system of licensed kava supply, controlled by local Aboriginal community organisations. Over the last decade, there has been an expanding global market for herbal preparations made in Western countries and containing kava extracts.4 These products have been marketed for the treatment of anxiety, insomnia, premenstrual syndrome and stress, and sold over the counter as complementary medicines or dietary supplements.6 Since 1999, cases of severe hepatic toxicity in people using kava-containing herbal products have been reported from Europe and the United States.6,7 Subsequently, kava-based herbal products have been banned in some European countries, including the United Kingdom. In Australia, a practitioner alert and consumer advice were issued in February 2002 by the Therapeutic Goods Administration (TGA) concerning hepatotoxicity possibly related to kava-containing products. By late 2002, eight cases of liver transplantation after hepatic failure associated with use of kava-containing products had been reported from Europe, and two from the United States.6 The patient reported by Gow et al died soon after liver transplantation.1 As a result of this case, the TGA initiated a voluntary recall of all complementary medicines containing kava extracts on 15 August 2002.8 The TGA has 87 products containing kava on its Australian Register of Therapeutic Goods.8 Although details are sketchy for many of the at least 68 cases of suspected kava hepatotoxicity,4 with the herbal products sometimes containing additional ingredients, the increasing number of well documented cases1,6,7 make it likely that kava extracts are responsible for occasional severe progressive hepatotoxicity. However, the mechanism of this toxicity remains to be determined. Histological examination has shown portal inflammation with lymphocytes and eosinophils,6,7,9 and an idiosyncratic immune response to a reactive metabolite has been suggested as a possible cause.9 In two patients, phenotyping of the activity of cytochrome P450 isoform CYP2D6 showed that they were "poor metabolisers", and it was postulated that genetic differences in liver metabolism of kavalactones may be important.9 Moulds and Malani discuss the paradox that fulminant hepatic failure has not been documented with traditional kava use in Pacific countries.2 Kavalactones in herbal products are usually extracted with ethanol or acetone,6 and may differ critically from the aqueously extracted kavalactones used in Pacific countries and Aboriginal communities. Of note is an early study of the health effects of kava use in Aboriginal communities, which documented consistent abnormalities in liver function tests in heavy kava drinkers.5 A recent study in Arnhem Land has confirmed these findings, with abnormal serum levels of γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in 61% and 50% of kava users, respectively.10 However, serum levels of alanine aminotransferase (ALT) were not raised in any kava drinkers. Furthermore, the abnormalities in liver function usually return to normal within 1–2 months of stopping kava use.10 The raised GGT and ALP levels combined with normal ALT levels in Aboriginal kava users do not suggest acute inflammation and are not consistent with the changes documented in the cases of hepatotoxicity associated with herbal products, where aminotransferase levels are especially high.1,6,7 Clinical surveillance in the Northern Territory over 20 years has not documented any cases of fulminant hepatic failure attributable to kava use. This is despite Aboriginal kava drinkers consuming kavalactones in doses estimated to be 10–50 times the recommended therapeutic doses for herbal products.3 However, the recent study confirmed adverse effects of kava, such as kava dermopathy and lymphocytopenia,10 which were documented in the 1980s.5 Although a rigorous systematic review found kava to be an effective symptomatic treatment option for anxiety,4 herbal preparations should not be used until the mechanism for hepatic toxicity is clearly ascertained. The abnormal but reversible GGT and ALP levels seen in heavy kava drinkers does not reflect the same pathological process. Whether the apparently idiosyncratic fulminant hepatic failure documented with herbal kava preparations can also occur with traditional aqueous extracts requires further surveillance. Close monitoring for this and other potential adverse effects of kava use in Aboriginal communities and Pacific countries is recommended, in addition to initiatives encouraging moderation in consumption.

Bart J Currie FRACP, DTMTH · Alan R Clough MSc

We describe a case of acute liver failure and death associated with the use of a preparation containing the "natural" anxiolytic kava (Piper methysticum) and passionflower (Passiflora incarnata). The patient died after a report by the Therapeutic Goods Administration (TGA) warning of the potential for hepatotoxicity associated with the use of kava-containing products. The general public and alternative medicine practitioners need to be aware of the potential for non-prescription drugs to cause serious hepatic reactions. Preparations containing kava (Piper methysticum) have become freely available in Australia and have gained widespread use as over-the-counter anxiolytics or sedatives. We report the first Australian case of fulminant hepatic failure associated with a kava-containing preparation. Clinical historyIn July 2002, a 56-year-old woman was referred to the Austin and Repatriation Medical Centre, Melbourne, for investigation of jaundice. She had been previously well apart from a history of benign monoclonal gammopathy (IgG, 24 g/L; normal, 6.9–15.4 g/L), which had been diagnosed 12 months previously. The patient had presented to her local doctor with a two-week history of fatigue, nausea and increasing jaundice. She had no risk factors for viral hepatitis, no history of liver disease and drank minimal amounts of alcohol. Over the preceding three months she had been taking a herbal supplement for anxiety, prescribed and provided by a naturopath (Kava 1800 Plus, Eagle Pharmaceuticals, Castle Hill, NSW; one tablet thrice daily, labelled as containing kavalactones 60 mg, Passiflora incarnata 50 mg and Scutellaria laterifloria 100 mg). She had also been taking some vitamin and mineral supplements but no other medications. Examination on presentation to hospital revealed the patient to be deeply jaundiced without stigmata of chronic liver disease. Relevant abnormal pathology test results are presented in Box 1. Extensive investigations to screen for recognised causes of acute liver failure failed to reveal any cause. Assays for acute hepatitis A, B, and C viruses, Epstein–Barr virus and cytomegalovirus were all negative. Serum copper and ceruloplasmin levels were normal and Kayser–Fleischer rings were not present. Antinuclear antibodies were detected at a titre of 1:160, but anti-smooth-muscle antibodies were not detected. No paracetamol was detected in the blood. An abdominal doppler ultrasound revealed a small liver with normal flow in the hepatic arteries, hepatic veins and portal veins. The paraprotein level had remained stable over the previous 12 months. A repeat bone marrow biopsy did not suggest the presence of multiple myeloma. A trans-jugular liver biopsy performed on the fifth day of admission showed non-specific severe acute hepatitis with pan-acinar necrosis and collapse of hepatic lobules. Over the subsequent week, the patient's condition deteriorated and she was urgently listed for transplantation. On Day 17 of admission the patient underwent liver transplantation. Unfortunately, the procedure was complicated by massive bleeding that did not correct following implantation of the donor liver, and the patient died of progressive blood loss, hypotension and circulatory failure. Histological examination of the explanted liver confirmed the presence of massive hepatic necrosis (Box 2). Subsequent analysis of the supplement she had taken revealed it contained kava and Passiflora incarnata as labelled, and a third, as yet unidentified, compound. Although the label listed Scutellaria laterifloria as an ingredient, none was identified in the compound. DiscussionThis case report describes the first case of fulminant hepatic failure in Australia in a patient after taking a product containing kava and Passiflora incarnata. We used the Naranjo Adverse Drug Reaction Probability Scale1 and found it was "probable" that the kava-containing preparation caused this patient's illness. Worldwide, at least 68 cases of suspected hepatotoxicity associated with the use of kava-containing products have been reported, including six resulting in liver transplantation and three deaths. Passiflora incarnata has also been described in association with the development of hepatotoxicity, but in only one case report, involving a patient who took several herbal medicines, including Passiflora incarnata.2 In February 2002 (despite the absence of any Australian reports of kava-associated hepatotoxicity), the Therapeutic Goods Administration (TGA) issued an alert regarding the potential hepatotoxicity of kava-containing products.3 This alert was widely distributed to doctors, pharmacists and alternative medicine practitioners. The patient we described began taking a kava-containing preparation after the TGA alert was issued, and apparently was unaware of the alert. Medication reactions resulting in abnormalities of liver function tests are relatively common, yet rarely result in severe liver injury. It is important to take a careful history of any drug or herbal remedy use in all patients with unexplained hepatitis, as the continuation of the agent after the onset of injury may have catastrophic consequences. Spontaneous recovery is unlikely in patients who develop encephalopathy or severe coagulopathy, and in such cases liver transplantation may offer the only realistic chance of survival.4 This report emphasises the need for the general public and alternative medicine practitioners to be aware of the potential for non-prescription drugs to cause serious hepatic reactions. The lack of regulation within the alternative medicine community and general availability of non-prescribed medications may have contributed to the death of this woman. A statutory obligation for dispensers of non-prescribed medications to provide information to the consumer at the point of sale regarding any future drug alerts may help to limit further morbidity and mortality. 1: Patient laboratory data on presentation to hospital and 17 days later (day of transplantation) Serum albumin (g/L) (normal, 35–50 g/L) Serum bilirubin (μmol/L) (normal, < 18 μmol/L) Serum alkaline phosphatase (U/L) (normal, 40–129 U/L) Serum alanine aminotransferase (U/L) (normal, < 55 U/L) International normalised ratio (normal, 1–1.2) Presentation 34 209 190 4539 2.3 Day 17 23 607 357 438 6.6 2: Histological section of the explanted liver The image shows an "empty" necrotic lobule which is devoid of hepatocytes (arrow). This is surrounded by proliferating bile ductules derived from portal tracts. Much of the liver had this appearance. (Haematoxylin and eosin stain; original magnification × 100. Image prepared by Mr Simon Rosalie.)

Paul J Gow FRACP, MD · Nathan J Connelly MB BS · Peter Crowley MB BS · Peter W Angus FRACP, MD · Richard L Hill MB BS

Following reports of liver toxicity, including liver failure, associated with extracts from the Pacific islands plant kava (Piper methysticum), these have been banned from sale as a herbal anxiolytic in many Western countries, to the detriment of Pacific island economies. Pacific Islanders have used kava extensively for centuries, without recognised liver toxicity. However, the population is small, and there has been no systematic evaluation of possible liver damage. For both economic and public health reasons, it is important to determine if kava is inherently hepatotoxic, and what the mechanisms of toxicity are. Such research could lead to safer kava extracts for sale in Western countries, or identification of a subpopulation who should not consume kava.

Robert F W Moulds PhD, FRACP · Joji Malani MB ChB

To the Editor: We wish to comment on the article by Whiting and colleagues1 on the proposed causal relationship between herbal remedies and severe acute hepatitis. Investigators have found that reported adverse effects of herbal medicines are not, in fact, caused by herbs alleged to be in the product, but result from substitution or contamination of the declared ingredients, intentionally or by accident, with a more toxic herb, a poisonous metal or even a pharmaceutical compound.2,3 In reports of adverse effects, there is often no effort to establish a positive identification of the herb involved or any adulterants. The attribution of toxicity to the wrong plant leads to inaccurate information being provided to patients, practitioners and regulators.4 A significant problem is the use of common names. As mentioned by Whiting and colleagues,1 Cimicifuga racemosa (black cohosh) has at least 20 different common names, which can be very confusing. The most tragic example of such confusion is the fatal substitution of Stephania tetrandra by the toxic herb Aristolochia fangchi owing to the similarity of the common names of the two herbs.5 In recording and responding to adverse events involving herbs, certain key questions need to be asked by those reporting the event and, more crucially, by those subsequently citing the report. No details regarding verification of the herbal products taken by the individual patients were supplied by Whiting and colleagues.1 Because of this failure to authenticate the plant compounds in the preparations, one cannot establish that the herbs were the cause of the hepatotoxicity. No information about plant parts used, solvent, concentration, manufacturing process or chemical analysis was supplied. Although Whiting et al exclude other causes for hepatitis, external factors may have contributed to the reported liver reactions. Hepatitis for which no cause can be identified is not uncommon.6 In addition, absence of hepatitis B surface antigen does not exclude the possibility of hepatitis B virus infection.7 The correlation of the liver diseases with preparations of Cimicifuga racemosa is speculative, as viral causes were not definitively ruled out. Without further pathophysiological or biochemical investigation, no conclusion can be made as to the exact mechanism. In a review of eight human studies on the effectiveness of an extract of black cohosh for alleviating menopausal symptoms, the authors concluded that black cohosh appears to be a safe, effective alternative to oestrogen replacement therapy for patients in whom oestrogen replacement therapy is refused or contraindicated.8

Luis Vitetta · Michael Thomsen · Avni Sali

Six patients presented with clinical, biochemical and histological evidence of severe hepatitis after taking herbal remedies. One patient required urgent liver transplantation for fulminant hepatic failure after the brief use of black cohosh. Five patients took a combination of herbs and presented with jaundice, fatigue and pruritus. Healthcare providers and members of the public should be aware of the potential adverse effects of these remedies. (MJA 2002; 177: 432-435) There has been a steady rise in the use of complementary medicine throughout the world. In 1997 it was estimated that 57% of Australians used complementary medicines, with an annual expenditure of $621 million.1,2 Self-medication is common, with 62%–72% of patients not disclosing the use of herbal preparations to their family doctors.3 This reluctance may be due to a perceived conflict between practitioners of conventional and alternative medicine. Although there have been trials on the efficacy of several herbal remedies, most information is based on anecdotal evidence and reputation. Information documenting adverse reactions is based on case reports and literature reviews, as there have been few prospective trials to date.4-7 As a result, the data available may not highlight potential adverse effects. In 1999 the Office of Complementary Medicine was created as part of the Therapeutic Goods Administration (TGA) in an attempt to regulate alternative medicine in Australia. The constituents of a herbal remedy must undergo pre-market evaluation for safety and quality before being listed on the Australian Register of Therapeutic Goods. Manufacturers of herbal products must now be licensed and need to adhere to the Therapeutic Goods Advertising Code. If a complementary medicine claims to "cure/manage or prevent" a disorder it requires high-level evidence to be registered, but if it claims to be for "symptom relief/health maintenance or health enhancement" then the product does not need formal evaluation. With the expanding use of these remedies, the risk of serious drug interactions increases. There is some information available on common interactions,7,8 but continued vigilance is required with the introduction of new medications. We describe six patients with hepatotoxicity from a variety of herbal remedies. The patients were reviewed by a gastroenterologist in Queensland (P K) between 1996 and 2001. Data were collected when the patient presented and subsequent telephone inquiry clarified any other details. The individual herbal products were not analysed for their constituents. Clinical recordsClinical records for the six patients are summarised in Box 1. One woman used black cohosh (Cimicifuga racemosa) alone for one week, and the other five patients were taking various combinations of herbs for 6–18 weeks before the onset of symptoms. Four patients disclosed the use of the herbal product to their general practitioner before referral. Patient 1 was taking the herbal remedy for relief of symptoms of menopause, Patient 5 as a "liver tonic", and Patient 6 to lose weight. The others took the remedies for general health promotion. The doses varied and were not reported to exceed the dosage recommended on the package. None of the patients had a history of excessive alcohol intake, injecting drug use, prior blood transfusion, family history of liver disease, or past history of liver or biliary tract disease. Patient 3 was taking temazepam, and Patient 4 had been taking long term low dose aspirin. No other concurrent medication was reported. Two patients had notable comorbidities: Patient 3 suffered from Huntington's chorea, and Patient 2 was diagnosed with ovarian adenocarcinoma shortly after presenting with hepatitis, but had no evidence of metastatic involvement of the liver on biopsy, computed tomography scan or at laparotomy. All patients developed jaundice, and the pattern of liver enzyme abnormality was predominantly hepatocellular (serum alanine aminotransferase level > 1000 U/L in each), with moderate elevations in the cholestatic enzymes. Pruritus was present in three patients. The international normalised ratio [INR] was elevated in two subjects (Patient 1: INR, 4.6; Patient 2: INR, 2.4). Peripheral blood eosino-philia was not present in any of the patients. No causes for liver disease other than the herbal remedies were found. Serology for hepatitis A (IgM, anti-HAV), hepatitis B (HBsAg) and hepatitis C (anti-HCV) was negative in each of the patients. The antinuclear antibody was positive in a titre of 1: 40 in Patients 2 and 3. The smooth-muscle antibody and antimitochondrial antibody titres were negative for all patients tested (1–3, 5, 6). The iron and copper profiles were in keeping with an acute phase response. The alpha-1-antitrypsin level was normal in all patients. An endoscopic retrograde cholangiopancreatogram demonstrated a normal biliary tree in two patients with jaundice and cholestatic features. All patients had normal imaging of the liver by upper abdominal ultrasound or computed tomography examination. Percutaneous liver biopsy was performed in five subjects with severe hepatitis, and the liver removed at transplantation (Patient 1) was available for study (Box 2). The biopsies were processed routinely, three sections were stained with haematoxylin–eosin, and additional sections were stained with haematoxylin–van Gieson. In all biopsies there was moderate to marked portal and lobular hepatitis. The limiting plates showed moderate to severe interface hepatitis (piecemeal necrosis). In addition, there was confluent zone 3 dropout and linkage of portal tracts and central veins. Eosinophils were present in five of the six cases but were not a conspicuous feature. All the biopsies were typical of acute hepatitis such as that seen in severe viral hepatitis. These changes are typically found in severe immunological reactions and are not the changes of direct toxic injury. Three patients with persistent jaundice and severe pruritus were treated with oral prednisone, resulting in immediate improvement in the symptoms of pruritus and jaundice. DiscussionHerbal remedies, like conventional medications, carry a risk of adverse reactions. There are many factors contributing to the potential toxicity of herbs. These include misidentification of the plant, variability in the time and place of collecting the plant, use of the wrong part of the plant, incorrect storage, contamination during preparation, and inconsistency in nomenclature and labelling of the final product.10 Adulterants such as corticosteroids have been added to some preparations.11 The remedies may have multiple ingredients, creating difficulty determining the causative agent and possible mechanism of injury. The identification of a herbal remedy as being responsible for hepatotoxicity often depends on demonstrating a temporal relationship between consumption of the product and development of the illness and improvement after discontinuation, after excluding other causes of liver disease. Some herbal agents used as medicinal products which are known to cause liver disease are listed in Box 3. We have identified six patients who developed abnormal liver function tests after taking herbal remedies. Other causes of liver disease were excluded. One patient required urgent liver transplantation, and the others recovered after stopping the herbal remedy. For ethical reasons, challenge experiments were not performed. Liver biopsies were characteristic of an idiosyncratic, immunological reaction24,25 and were very similar to the changes seen in acute viral hepatitis. In particular, there was prominent hepatocyte apoptosis, acinar zone 3 dropout, and at least focal bridging "necrosis" in all cases. This pattern of injury has been noted with skullcap and valerian,19 but differs from the liver injury described with chaparral12 and germander,14 where true coagulative necrosis rather than apoptosis is observed (suggesting toxic injury and not an immunological reaction). The most serious illness occurred in a 47-year-old woman (Patient 1) who was taking black cohosh for symptoms related to the menopause. Histological examination of her explant liver confirmed severe hepatitis and multiacinar dropout. The large number of synonyms for black cohosh highlights the problems with nomenclature, with up to 20 names used in North Carolina and South Carolina alone.11 It is widely used, particularly in Europe, for its putative beneficial influence on perimenopausal symptoms.26 In the United States, the Food and Drug Administration (FDA) lists it as a "herb of undefined safety".27 There are no restrictions on the use of black cohosh in Australia. It contains a mixture of alkaloids, tannins and terpenoids, and has not previously been reported to have hepatotoxic effects. Diterpenoids have been shown in animal models to result in liver injury, either by reactive metabolites or by an auto-immune mechanism.7 Previous studies have incriminated mixtures of skullcap and valerian as causing hepatitis,13,19 with jaundice and marked elevation in serum bilirubin and alanine amino-transferase levels being features. In our series, two patients (2 and 3) were using this combination and a further patient (4) used skullcap without valerian. In addition, the mixture Patient 2 took also contained black cohosh. Patient 5 was taking a combination of herbs that included chaparral. Chaparral, when taken in capsule or tablet form, can cause subacute hepatitis, but no deaths have been reported.12 In 1992, the FDA issued a warning about the potential danger of its use. There are no reported cases of the other herbs being hepatotoxic. Patient 6 was taking a preparation containing a mixture of herbs advertised as a fat metaboliser and a fluid retention remedy. Greater celandine (Chelidonium majus) has been associated with acute hepatitis characterised by marked cholestasis.15 Buchus leaf contains pulegone, a volatile oil also found in pennyroyal oil. Pulegone has been reported to be hepatotoxic,28 either directly or via a reactive intermediate.29 The true incidence of hepatic damage caused by herbal medications remains unknown owing to a lack of prospective studies. The incidence of hepatotoxicity from Chinese herbal remedies has been estimated at between 0.2% and 1%.30 With the increasing use of herbal remedies, medical practitioners need to be aware of the potential adverse effects and should routinely ask patients about all medications, including herbal mixtures. Labelling and advertising should include the known adverse effects, and a public education program is needed so that consumers are more aware of potential risks. The establishment of the Office of Complementary Medicine should address some of these issues. Finally, toxicity testing for plants and herbs used therapeutically should be undertaken as for manufactured drugs. 1: Summary of clinical and laboratory data for six patients who developed hepatitis after taking herbal remedies Patient (sex, age) Herbal remedy Time on herbs (weeks) Time to symptoms (weeks) Symptoms Peak value Time from diagnosis to normal laboratory results (weeks) Treatment Symptom Duration(weeks) Bilirubin† (μmol/L) ALP‡ (U/L) AST§ (U/L) ALT¶ (U/L) GGT** (U/L) 1(F, 47) Black cohosh 1 1 Jaundice 2 335 158 3182 2295 163 Not applicable Liver transplant 2(F, 43) Skullcap;* valerian;* black cohosh; passionflower; Angelicia sinensis; hops; Avema sativa; chasteberry N/A N/A Jaundice; nausea; vomiting; diarrhoea 18 284 80 1140 1500 N/A N/A Nil 3(F, 75) Skullcap; valerian;* hops 6 6 Jaundice 4 169 219 933 1470 330 20 Nil 4(M, 55) Skullcap; Ginkgo biloba 14 18 Jaundice; pruritus 5 181 150 1018 1293 373 7 Prednisone 5(M, 25) Chaparral;* dandelion; Withania somnifera; horsetail; echinacea 6 8 Jaundice; pruritus; fatigue 4 684 159 3910 3104 318 7 Prednisone 6(F, 23) Greater celandine;* buchus leaf; Uva ursi; juniper; parsley piert; choline bitartrate; dandelion 12 12 Jaundice; pruritus; fatigue 5 1073 134 2092 3764 81 25 Prednisone * Herbal remedies reported as hepatotoxic (see Box 3). † Bilirubin normal range < 20 μmol/L. ‡ Alkaline phosphatase (ALP) normal range 40–250 U/L. § Aspartate aminotransferase (AST) normal range < 35 U/L. ¶ Alanine aminotransferase (ALT) normal range < 40 U/L. ** Gamma glutamyltransferase (GGT) normal range < 50 U/L. N/A = not available. Botanical names: Black cohosh, Cimicifuga racemosa; Skullcap, Scutellaria lateriflora; Valerian, Valeriana officinalis; Passionflower, Passiflora incarnata; Hops, Humulus lupulus; Chasteberry, Vitex agnus-castus; Chaparral, Larrea tridentata; Dandelion, Taraxacum officinale; Horsetail, Equisetum arvense; Greater celandine, Chelidonium majus; Juniper, Juniperus communis. 2: Liver histology for the six patients* Patient Interface hepatitis (0–4) Portal inflammation (0–4) Zone 3 hepatocyte loss (0–4) Bridging necrosis (0–2) Lobular inflammation (0–4) Eosinophils (0–2) Bile duct damage Fibrosis (0–6) 1 ++ ++ ++++ ++ ++ ++ 0 Early 2 ++++ ++++ +++ focal ++++ ++ 0 0 3 +++ ++ ++++ + ++++ + 0 Early 4 +++ ++ +++ focal +++ 0 0 0 5 +++ +++ +++ focal ++++ ++ 0 0 6 +++ +++ ++++ + ++++ + 0 0 * Scoring system adapted from Ishak et al.9 Eosinophils 0 = none; 1 = 1–4 per portal tract; 2 = > 4 per portal tract. 3: Common herbal remedies suspected of being hepatotoxic Common name Botanical name Potential toxic constituents Indications Hepatic disease References Chaparral Larrea tridentata Nordihydroguaiaretic acid Free radical scavengerDelays aging Hepatitis Gordon et al (1995)12 Comfrey Symphytum officinale Pyrrolizidine alkaloids Herbal teaPoultice Veno-occlusive diseaseHepatic adenomas Miskelly et al (1992)13 Germander Teucrium chamaedrys Furano neoclerodaneFlavonoids Antipyretic Weight control Hepatitis Larrey et al (1992)14 Greater celandine Chelidonium majus Unknown Gallstones Dyspepsia Hepatitis Benninger et al (1999)15 Jin Bu Huan Lycopodium serratum Unknown Sedative Analgesic Hepatitis Graham-Brown (1992)16 Kombucha tea Kombucha "mushroom" Unknown Arthritis Cancer cure Hepatitis Perran et al (1995)17 Mistletoe Viscum album Unknown Antihypertensive Sedative Hepatitis Harvey and Colin-Jones (1981)18 Mixtures of valerian and skullcap Valeriana officinalis Scutellaria lateriflora Alkylating agents Crystalline glycoside and a volatile oil Sedative Sedative Hepatitis Hepatitis MacGregor et al (1989)19 Miskelly et al (1992)13 Pennyroyal oil (squawmint oil) Labiatae spp. Pulegone Abortifacient Menstrual complaints Hepatic necrosis Anderson et al (1996)20 Sassafras Sassafras albidum Safrole Arthritis Hepatitis Hepatocarcinogen Segelman et al (1976)21 Senna Cassia angustfolia Sennosides Laxative Hepatitis Beuers et al (1991)22 White chameleon Atractylis gummifera Potassium atractylate Gummiferin Antipyretic Purgative Hepatitis Georgiou et al (1988)23

Peter W Whiting MB BCh, BAO, FRACP · Andrew Clouston MB BS, PhD, FRCPA · Paul Kerlin BA, MD, FRACP