Digestive system diseases

A 39-year-old woman with AIDS (CD4 count, 30 cells/mL) had a 4-day history of nausea, vomiting and profuse watery diarrhoea. The patient was afebrile and had a distended abdomen with diffuse guarding without rebound tenderness. Abdominal x-rays (Box 1) and computed tomography scans (Box 2) were performed. The white blood cell count was within normal limits and stool cultures were negative. Colonoscopy revealed yellow plaques throughout the colon. The patient improved clinically after taking oral metronidazole. Bowel wall "thumbprinting" (the appearance of "thumbprint"-shaped projections) is a radiological sign of thickening of the colonic wall. It occurs secondary to submucosal haemorrhage and oedema from capillary leakage.1 It can result from any process that leads to oedema of the bowel wall, including pseudomembranous colitis (as shown here), ischaemic colitis, non-infective inflammatory bowel disease, other infective bowel diseases, submucosal/intramural haemorrhage and other conditions.2 The mucosal damage and inflammation seen in pseudomembranous colitis are caused by Clostridium difficile toxin.3

Moishe Liberman MD · Chris Labos · Jeff Wiseman MD

Crohn's disease is an important cause of morbidity in Australia, with a prevalence of about 50 per 100 000 population. The disease is most common in adolescents and young adults, but can occur at any age. The cause is still unknown, but research towards finding the cause is proceeding apace, along with improvements in diagnosis and advances in therapy. The development of Crohn's disease depends upon an ...

Warwick S Selby MB BS MD FRACP

Objectives: To determine the utility of capsule endoscopy in patients referred for investigation of suspected disease of the small intestine.Design and setting: Single centre, prospective, cohort study from 4 July 2001 to 8 September 2002.Patients: Sixty consecutive patients who underwent capsule endoscopy for investigation of suspected disease of the small intestine.Main outcome measures: Abnormal findings at capsule endoscopy.Results: ...

André K H Chong FRACP · Andrew C F Taylor MD, FRACP · Ashley M Miller PhD, FRACP · Paul V Desmond FRACP

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

Aim: To determine effectiveness of treatment for hepatitis C outside clinical trials, by testing the hypothesis that apparent effectiveness and tolerability of interferon alfa-2b/ribavirin combination therapy would be less in a hospital liver clinic setting.Design: Retrospective analysis of all patients in one centre commencing interferon alfa-2b/ribavirin therapy, but not in clinical trials, between 1998 and 2000.Main outcome measures: Effectiveness as sustained virological response (SVR); tolerability as premature discontinuation of treatment.Results: The 121 patients had similar demographic and viral characteristics as those in Australian trials (age, 44 ± 10 years; males, 66%; genotype 1, 44%; genotype 3, 36%), but 38% had advanced fibrosis, including 17% with cirrhosis. Sixty (50%) were previously untreated, 38 (31%) had relapsed after initial response (response relapse) and 23 (19%) were non-responders to interferon monotherapy. Sustained viral response (SVR) was achieved in 53% of patients overall: 47% of patients with genotype 1 HCV, 71% of patients with genotype 3. For patients with genotype 1 HCV, SVR was 43% in those previously untreated, 63% in response relapsers, and 38% in non-responders. Corresponding SVRs for genotype 3 were 65%, 87% and 33%. These results are similar to those obtained in published trials. Only 7% of our patients discontinued treatment because of adverse effects, fewer than reported in most clinical trials. Dose reduction was required in 18% of patients.Conclusions: In a hospital clinic setting the effectiveness of interferon alfa-2b/ribavirin combination therapy appears equivalent to published results from clinical trials.

Dinesh Kumar* MD, DM · Craig Wallington-Beddoe* BSc, MB BS · Jacob George PhD, FRACP · Rita Lin PhD, FRACP · Dev Samarasinghe PhD, FRACP · Chris Liddle PhD, FRACP · Geoffrey C Farrell MD, FRACP

Chronic HBV infection is common in remote Aboriginal and Torres Strait Islander communities, where resources are scarce and patients may have several concurrent illnesses. The management of chronic HBV infection has changed over recent years, with greater application of serological and radiological investigations and new, more acceptable treatments for chronic liver disease, cirrhosis and hepatocellular carcinoma. Optimal follow-up procedures for patients with chronic HBV infection are still being debated, but may not be applicable to Aboriginal and Torres Strait Islander communities where factors such as endemicity, remoteness, frequent comorbidities, shorter life expectancy and cultural differences in health priorities must be taken into consideration. We have defined an algorithm to assist primary care providers caring for patients with chronic HBV infection in Aboriginal and Torres Strait Islander communities. Patients are divided into one of three categories for follow-up and referral based on clinical features, and results of liver enzyme and serological tests.

Dale A Fisher FRACP · Sarah E Huffam FRACP

To the Editor: Colorectal cancer is, after skin cancer, the most common cancer in Australia, with 11 245 new cases diagnosed in 1997, and over 4600 deaths.1 In clinical trials, screening programs using faecal occult blood testing (FOBT) have been shown to reduce mortality. The Commonwealth Department of Health and Ageing estimates that implementation of effective FOBT screening programs would save around 400 lives per year.1 However, such screening programs have not been widely implemented because of perceived difficulties with patient acceptance, funding, and the complexity of support structures. General practitioners are in the front line of healthcare, and well placed to institute FOBT screening. Thus, we established an opportunistic screening program whereby patients over the age of 50 years attending surgery are asked by reception staff to complete a short questionnaire while in the waiting room. This questionnaire, developed locally to quickly establish whether a patient has symptoms or a family history of bowel cancer, is given to the GP by the patient during the consultation. If the questionnaire indicates colorectal symptoms, appropriate clinical assessment is undertaken. If a family history of colorectal cancer is elicited, the GP further defines the patient's risk by using the established National Health and Medical Research Council guidelines.2 If there are neither symptoms nor a family history, the patient is offered annual FOBT screening. From 17 June to 30 September 2002, 731 patients under the care of 29 GPs completed the questionnaire. Our findings are summarised in the Box. GP-based opportunistic screening can reach significant numbers of people. Moreover, unlike other strategies (eg, distribution of test kits by pharmacies), review by GPs of patients' questionnaires ensures that cases unsuitable for FOBT screening (such as those with previously undeclared symptoms or family history) are appropriately assessed. Data reported so far on patients who completed general practice questionnaires for eliciting family history or symptoms of bowel cancer FOBT = faecal occult blood testing.

Susan J Harnett · SK Cyril Wong · Gavin W Lackey

Hepatitis C. An Australian perspective. Nick Crofts, Greg Dore and Stephen Locarnini (editors). Melbourne: IP Communications, 2001 (xviii + 380 pp). ISBN 0 9578617 2 9. This book is an excellent resource for healthcare professionals who work with hepatitis C, and for people suffering from this condition who wish to have access to detailed, up-to-date, technical information. The book is multi-authored and its main strength is its well-chosen authors — they are all Australian experts. Scott Bowden (Senior Scientist at the Victorian Infectious Diseases Reference Laboratory) has written a comprehensive chapter on laboratory diagnosis. He explains clearly the difficulties in comparing the two assays used for quantifying viral load, and the differences between the various serological assays. William Sievert, of Monash Medical Centre, has contributed an excellent chapter on antiviral treatment, with up-to-date information on newer treatments, and predictors of response. Margaret MacDonald, Nick Crofts, Alex Wodak and John Kaldor have written the chapter on hepatitis C transmission. Nick Crofts has expanded on transmission in a subsequent chapter entitled “Descriptive epidemiology of the hepatitis C virus”. This chapter provides an interesting and detailed review of global trends in hepatitis C. As well as technical sections on virology, pathogenesis, treatment and epidemiology, there are excellent sections on quality of life, discrimination, policy and prevention. There are always areas where an individual reviewer will see omissions. Liver transplantation is not described in any detail — many readers would like to know whether transplantation has a role, and what its success, limitations and implications are. Similarly, there is not much information on “the next ten years” in antiviral treatment. The chapters on policy and prevention are excellent, but do not address some of the gaps in current policy and practice. For example, the apparent ineffectiveness of harm reduction programs in significantly reducing the prevalence of hepatitis C is not considered, nor are the lack of culturally appropriate education or treatment facilities for ethnic groups and the lack of resources in rural areas. I hope that the positive foreword written by the former Federal Minister for Health, Dr Michael Wooldridge, indicates an ongoing commitment by government to address some of these issues. It will be interesting to see whether these gaps have been closed by the time a second edition is published in a few years’ time (as I hope it will be). A manageable size at 350 pages, the book is well referenced, well indexed and, at $85, well worth the price. Katrina J R WatsonGastroenterologist St Vincent’s Hospital, Fitzroy, VIC

Katrina J R Watson

Left to right: Professor John Tyrer with three of his "disciples" — Mervyn Eadie, myself and Bryan Emmerson — taken in 1999 when I retired as Director of QIMR. As I reflect on my professional career, the one word that repeatedly springs to mind is "mentorship". I have been fortunate in having had truly remarkable mentors at several key points in my career. Family firstThe first was my father, who, while not university educated, was an intelligent man who ran the family printing business. His professional contacts convinced him of the importance of a sound education for his only son, and when I declared an interest in Medicine and Law he suggested that the two in combination would be very useful. I chose Medicine — in part, because I was intrigued by our family illnesses and surmised that an insight into them would be of benefit to the whole family. This, of course, proved correct. Throughout my school and university years, my mother suffered from post-encephalitic parkinsonism. This placed a great burden on my younger sister, who undertook the family's domestic responsibilities when still in high school. My father died during my fourth year of medical studies and my mother soon after my graduation. Local heroesMy next influential mentor was Frank Garlick, a perspicacious surgeon at the Royal Brisbane Hospital (RBH). It was he who, in 1956, detected a spark of enthusiasm for inquiry and research in a young medical student and so encouraged me to pursue my then interest in malignant melanoma. My dissertation (published in Trephine, the annual magazine of The University of Queensland's Medical Students Society) won the prize for the best research project by an undergraduate student at the university's medical school, and this experience kindled my life-long interest in medical research. After Garlick came John Tyrer, who had not long been appointed to the first full-time chair of medicine at The University of Queensland based at the RBH. Tyrer steadily built a strong department of medicine, having had the foresight to create several "temporary clinical lectureships". These positions were filled by aspiring medical registrars who had successfully negotiated the hurdle of membership of the Royal Australasian College of Physicians, and provided them with the opportunity to combine clinical responsibilities with research — usually towards an MD thesis. It is interesting to reflect on the number of people who spent their formative years being nurtured in such positions who subsequently went on to become academic leaders in Australia. They include Bryan Emmerson (rheumatologist, professor of medicine and head of the department, based at the Princess Alexandra Hospital, Brisbane, 1985–1994) and Mervyn Eadie (neurologist, professor of medicine and head of department at Royal Brisbane Hospital, 1994–1997), to name but two. I greatly lament the fact that, during the 1980s, these positions were abolished progressively as increasing financial constraints affected the university. It was as a temporary clinical lecturer that I found myself fascinated when I realised that four young women with haemochromatosis were from the same family. The literature at that time indicated that the disease was rare in women, especially premenopausal women, and that it was usually due to excess alcohol consumption. These women were all teetotallers, firing up my interest in challenging the existing dogma. Encouraged by Tyrer and his deputy, Martin Lloyd, I undertook a systematic study of iron metabolism in families of patients with haemochromatosis and families of patients with alcoholic cirrhosis.1 This, together with some rather tedious animal studies in iron-loaded rabbits, eventually led to a successful MD thesis and several publications, one of which occasioned an editorial in The Lancet.2 But, more importantly, these achievements provided me an opportunity to work with the doyenne of liver disease, Professor (later Dame) Sheila Sherlock — again following overtures made by John Tyrer on my behalf. International influenceMuch has been written about Sheila Sherlock and her enduring influence on aspiring hepatologists from many countries, including the many obituaries published following her death last year.3,4 In 1965, I was just one of some 20 research fellows — from countries far and wide, including the USA, South Africa and Asia — working in her unit, located in wooden huts up on the roof of the Royal Free Hospital in Gray's Inn Road, London. Sheila took a sincere personal interest in each of us and our careers. Given my published work in haemochromatosis and iron metabolism, Sheila resolved that I should "broaden horizons". She suggested I tackle the topical subject of bilirubin metabolism and Gilbert's syndrome with Barbara Billing, who had recently joined the unit as its only basic scientist. It was an enjoyable and productive association that added new information on haemolysis and Gilbert's syndrome, which Sheila quickly put into clinical perspective.5 Barbara Billing herself was also an excellent mentor and taught me a great deal about laboratory research. Like other fellows in the unit, I was not only exposed to the whole repertoire of liver disease, but also Sheila Sherlock's brilliant clinical acumen and lucid thought processes. Sherlock made a particular effort to train her fellows to present their work at meetings clearly without notes, and set an example by always rehearsing her own major lectures and speeches with staff members and research fellows. Her clarity of communication was legendary. She would convert an amateurish first draft into a manuscript promptly accepted by the New England Journal of Medicine — without revision! She exposed us to "the big names". I felt privileged to be sent to Caroli's unit in Paris to lecture on our work (Caroli, the famous French hepatologist, is noted for Caroli's disease, a congenital cystic dilatation of the intrahepatic bile ducts and associated disorders). Most of her fellows had similar experiences. My subsequent international training, some years later, was equally important but different and complementary. In 1972–1973, Kurt Isselbacher — at that time chief of gastroenterology at Massachusetts General Hospital (MGH) and Harvard Medical School — introduced me to North American academic medicine and laboratory science. Kurt was yet another active mentor, involving me in giving lectures to Harvard medical students, presenting medical grand rounds at MGH, and a harrowing experience as discussant at one of the weekly clinicopathological conferences, published, as usual, in the New England Journal of Medicine.6 The case was one of cholestasis and cholangitis in a man with alpha-1-antitrypsin deficiency. He also recruited me as a contributor to Harrison's Textbook of Medicine, a unique opportunity. I have continued to contribute to each subsequent edition of the book as author of the chapter on haemochromatosis.7 In 1978, a sabbatical at the Rigshospitalet in Copenhagen with Niels Tygstrup — renowned for his extensive work on quantitative tests of liver function — broadened my horizons once again. His unit had strong expertise and interest in basic immunology as it applied to the liver, adding a further dimension to my perspective of international hepatology. Back in AustraliaIn 1966, I had been fortunate in securing a senior lectureship in the department of medicine at The University of Queensland and the Royal Brisbane Hospital. The next vacancy did not occur until eight years later! The department had been progressively strengthened by Tyrer, and was arguably the most productive department in the biological sciences and medicine faculties at the university. With my two inspired colleagues, June Halliday and Graham Cooksley, I established the first academic liver unit in Australia, which, over the years, attracted numerous scholars, both science-based and medical, each adding stimulus and challenge. These scholars included, among others: Geoff Farrell, head of the Storr Liver Unit in Sydney; Mark Bassett, gastroenterologist and associate professor, the Canberra Hospital and Clinical School; Keith Tolman, head of gastroenterology at Utah Medical School, Salt Lake City; and Paul Adams, an international authority on haemochromatosis, from Ontario, Canada. Our research focus was, of course, on haemochromatosis and iron metabolism, with our original research contributions opening doors to both the International Association for the Study of the Liver and the biennial meetings on iron metabolism. Fortunately, these international meetings were held in alternate years. Graham Cooksley later extended our research repertoire to include the immunology of liver disease and then viral hepatitis. Our combination of two physician scientists with a full-time NHMRC-funded basic scientist proved a successful formula. We were awarded an NHMRC program grant (iron metabolism and liver disease) in 1982 that was renewed at every subsequent quinquennial review until it was incorporated into the block grant for the Queensland Institute of Medical Research in 1998 (see below). During this period, I was privileged to be elected President of the International Association for the Study of the Liver. We hosted the World Congress of Iron Metabolism twice: in 1989, in Brisbane, and in 2001, in Cairns; we also hosted the Biennial Scientific Meeting of the International Association for the Study of the Liver in 1990 on the Gold Coast. The Queensland Institute of Medical ResearchLeft to right: Graham Cooksley, myself, June Halliday and John Tyrer — in 1982, at the announcement of the NHMRC Program Grant. In 1988, I undertook my last sabbatical at the Queensland Institute of Medical Research (QIMR). This experience allowed me to become acquainted with the Institute's staff and science and successfully apply, in 1989, to become its Director. The 10 years that followed are now history, but I still find it interesting to reflect on the developments that occurred at QIMR during that time. My predecessor, Chev Kidson, had made significant advances by linking the Institute with The University of Queensland (rather than the State health department) by recruiting some high quality staff, and by securing funding from the Queensland government for a new purpose-built 11-storey institute — the Bancroft Centre. The Centre was opened by the then State Premier, Wayne Goss, in 1991. This new facility allowed a fivefold expansion of the Institute, achieved smoothly over the next five years. Queenslanders were recruited back from overseas, including Graham Kay, who established QIMR's transgenic facilities. Others came from the southern Australian States, notably Anne Kelso and Andrew Boyd among those recruited from the Walter and Eliza Hall Institute, with the assistance and strong support of Sir Gustav Nossal. The Liver Unit — myself, June Halliday and Graham Cooksley and some 25 staff — moved en bloc into the Bancroft Centre (Graham as Director of the Clinical Research Centre of the Royal Brisbane Hospital Foundation, which was also situated in the building). It soon became apparent that the expanding Institute would benefit from independent peer review. In 1994, with the strong support of Judy Whitworth, then chair of the research committee of the National Health and Medical Research Council (NHMRC), I was able to put together a formidable review committee. Chaired by Keith Peters, chairman of the department of medicine at Cambridge University, UK, and including Peter Doherty (then professor of immunology at St Jude's Hospital for Children, Memphis, Tennessee), Bob Williamson (then professor of biochemistry, St Mary's Hospital, London), the committee included three Australians. Professors Fiona Stanley (the Institute for Child Health, Western Australia), Richard Smallwood (professor of medicine, the Austin and Repatriation Hospital, Melbourne) and Ashley Dunn (the Ludwig Institute, Melbourne) were all nominated by the NHMRC. A week-long in-depth review by this committee made a huge impact on the strategy and further research directions adopted by the Institute. I also believe that this committee influenced the NHMRC with respect to block funding. Its last term of reference, clearly the most challenging, was to address whether QIMR should apply for block funding. After deliberation, the committee concluded that, "in the Australian context", QIMR should indeed apply to the NHMRC for block funding. However, it was also clear that the largely international committee saw significant disadvantages in block funding. Keith Peters conveyed these sentiments, at the time, to Judy Whitworth. Interestingly, since 1998, NMHRC block funding has been progressively abolished and the program and project funding system restructured. As a result, total NHMRC funding to the QIMR (including program grants, project grants and fellowships) has increased from $6.0 million in 1998 to $7.82 million in 2002 — an increase of about 30%. The "White Knight"By 1996, the "new" Bancroft Centre was fully occupied and we dreamed of new ways to expand the Institute. All were futile until, in 1998, the fortuitous juxtaposition of two "once-in-a-lifetime" events enabled us to realise our dream. Firstly, we were approached, anonymously, by a US organisation — which we later found out was Atlantic Philanthropies in New York — after they had conducted an independent assessment of the Institute. After protracted discussion with their Dublin-based consultant, two visits by him, and submission of a detailed business plan, we were advised that their board would support our "dream", with a donation of $20 million, conditional on our raising the remaining $35 million required within six months! Of course, this proved a difficult challenge, but with the bipartisan support of the Queensland government ($20 million), the assistance of the Leukaemia Foundation ($5 million) and the QIMR Trust ($10 million) the target was achieved. The second fortuitous event was the concomitant rebuilding of the Royal Brisbane Hospital and the Royal Women's Hospital, which released space for a new building close to the Bancroft Centre. State authorities graciously provided the space to QIMR and the new 10-storey Comprehensive Cancer Research Centre was completed in 2001. Soon afterwards, Mr Clive Berghofer (a Queensland grazier and real estate developer) generously donated $5 million for the naming rights for 10 years — a rare occurrence in Australian science! A special feature of the development has been the inclusion of a clinical trials centre occupied and administered by QPharm, a newly established independent company that conducts phase I clinical trials of new compounds. State authorities have also granted QIMR the former Queensland Radium Institute (QRI) building, available from 2004, which lies between the old and new QIMR buildings. Thus, when fully developed, the new QIMR will occupy three buildings and have a total staff of over a thousand. A new eraThe new Queensland Institute of Medical Research (QIMR) (left), incorporating the Bancroft Centre, and the Clive Berghofer Comprehensive Cancer Research Centre, with the former Queensland Radium Institute building in between. From 2004, QIMR will comprise all three buildings. In 2002, on retiring from the QIMR, I was invited to become the Director of Research at the redeveloped Royal Brisbane and Royal Women's Hospital — in some respects, a position more challenging than Director of QIMR! While I continue to enjoy some clinical practice and teaching, the challenge to stimulate research in the hospital environment is formidable. For decades, the RBH has been the flagship of Queensland's hospital health and medical research effort, but financial stringencies of recent years have indeed taken their toll. While Australian medical research institutes have increased in size and number over the past 10 years, university departments, and particularly our teaching hospitals, have found it increasingly difficult to fund research. Moreover, with ever-increasing clinical demands, less time for research and uncertain career paths, I believe young graduates are now discouraged from embarking on clinical research or a career in research or academia. Although this is, to some extent, a global problem, it is so particularly in Australia, where, for example, in contrast to Canada and the USA, there is a very significant difference between stipends for research fellows as opposed to those in clinical posts. I sincerely hope that current efforts by the NHMRC and others to boost clinical research, such as with the introduction of NHMRC practitioner fellowships and the NHMRC Centres of Clinical Excellence Program, will be successful. Thus, I am delighted that the potential gap between basic and clinical research has been bridged at QIMR. The Institute's present Director, Michael Good (with an international reputation in the immunology of infectious diseases), and Deputy Director, Adèle Green (an internationally acclaimed epidemiologist), are both medically qualified scientists; as well, several of the research staff have clinical appointments at the Royal Brisbane Hospital. The Institute's research portfolio now spans the full spectrum, from fundamental molecular research to clinical translational research and clinical trials and, more recently, a research program in Indigenous health. ConstanciesNone of my contributions would have been possible without the devotion and enduring support over 42 years of my wife, Margaret (née Ingram), herself a University of Queensland graduate in education. Margaret has not only raised and nurtured five children, fostering their university education (in medicine, education, psychology, environmental science and music), but has also taken them around the world during my extensive years of training and study leave. Also, it should be apparent that I feel and have always felt passionately about two themes — the importance of mentorship in medicine and biomedical science, and bridging basic science and clinical medicine (from the bench to the bedside and back) to produce clinically relevant research. It is because young researchers were inspired by their mentors that clinical science, and indeed clinical medicine, have become what they are today, and this needs to continue. The importance of this practice has been enunciated well by Dean William Welch, of Johns Hopkins fame, who wrote: Let us not forget that a university or a medical college may have large endowments, palatial buildings, modern laboratories, and still the breath of life may not be in it. The vitalising principle is in the men (and women) — both teachers and students — who work within its walls. Without this element of life, this bond between teacher and taught, these things are but outward pomp and show. But let these greater opportunities receive the breath of life from the inspiration of great teachers and they then become the mighty instrument of higher education and scientific progress.8

Lawrie W Powell AC, FTSE, MD, PhD, FRACP, FRCP, FRCPT

To the Editor: Bolin et al,1 in their editorial accompanying articles by Yusoff et al2 and Bampton et al,3 took the opportunity to make their case for endoscopic screening for colorectal cancer. We believe that their editorial is seriously misleading. 1: It is misleading to suggest that the 27 case–control and cohort studies in the meta-analysis by Johns and Houston4 stratified the index case by age at diagnosis. The 2.25 risk quoted by Bolin et al refers to the overall risk of first-degree relatives in families with one affected relative. In those studies in which age was stratified in the meta-analysis, there is a spectrum of risk, with families with onset of bowel cancer at an older age having lifetime relative risks much less than the average. A subanalysis of seven studies with age stratification showed the risk to be 1.82 (95% CI, 1.47–2.25), where the index case was over 59 years at diagnosis. Whether a 1.8-fold risk elevation warrants colonoscopic surveillance could be debated. "First do no harm" is an important axiom in well-patient screening, so one should aim for an order of magnitude of benefit over risk, which in this situation is not secured until the patient being screened is older than the suggested 40 years of age. 2: The recommendation that colonoscopic follow-up of patients with only small, tubular, distal adenomas can be at less frequent intervals is not based on the US National Polyp Study,5 as suggested in the editorial. It is based on the large cohort study of Atkin et al,6 who reported that patients with this finding were actually at below-average risk (relative risk, 0.5) for subsequent colorectal cancer after prolonged follow-up. This occurred despite the inevitable "miss rates". The editorial by Bolin et al handles this issue unconvincingly. The main message of the US National Polyp Study5 was that follow-up (except in exceptional circumstances of numerous polyps, or incomplete removal of malignant polyps) is not needed at 12 months — after 3 years is adequate. The National Health and Medical Research Council guidelines extend this to 4–6 years in the low risk groups, as defined by Atkin et al.6 The Atkin et al data, however, are only Level 3 evidence. 3: Bolin et al1 completely miss the point about pilot programs of screening with faecal occult blood testing (FOBT). There is no intention to confirm evidence of mortality reduction. The pilot studies are neither designed to, nor capable of, doing this. Mortality reduction from FOBT is well established on Level 1 evidence. The pilot studies are in place to answer the very practical questions of how to implement large-scale screening programs in Australia; what logistic and resource issues are involved; how compliance and acceptance will best be secured; and how to approach difficult-to-access populations (perhaps with low health insurance rates as distinct from populations well supplied by colonoscopy services). The central issue in advocating a menu of options to individuals versus more prescriptive screening (based on FOBT) is whether the height of the scientific bar should be at Level 1 evidence or modestly robust Level 3 evidence (flexible sigmoidoscopy) or the less robust Level 3 evidence (colonoscopy), complemented by certain appeals to logic (carefully crafted in the editorial). Medical initiatives based on less than Level 1 evidence have a history of being shown to be wrong, and the concept of colonoscopic surveillance is not immune from this outcome. Where a significant outlay from the public purse is involved, the Federal Government is being appropriately prudent in acting on Level 1 evidence.

Finlay A Macrae · Geoffrey S Hebbard

In reply: Macrae and Hebbard fail to grasp the concept that colorectal cancer is the only potentially preventable cancer in men and one of the two preventable cancers in women. In any discussion about screening options, this fact must be kept clearly in focus. In terms of surveillance of first-degree relatives, we doubt the available evidence is of sufficient quality to be certain whether the absolute risk is 1.82 or 2.25. In either event, we would advocate colonoscopic surveillance. We would, however, agree with Macrae and Hebbard on the importance of safety issues. Elsewhere we have advocated confining the performance of colonoscopies to endoscopists with Conjoint Committee Accreditation, and ensuring that the procedures are undertaken in accredited, suitably equipped facilities.1 We find it difficult to understand why Macrae and Hebbard believe that "the main message of the US National Polyp Study2 was that follow-up . . . is not needed at 12 months". Showing a reduction in expected cancers of 90% seems to us a far more important finding. We would, however, point out that our editorial does not advocate routine colonoscopic follow-up at 12 months. In relation to the pilot faecal occult blood testing (FOBT) studies, we believe that Macrae and Hebbard have missed the point. They advocate delaying colorectal cancer screening for a further five years to await the results of studies which, many believe, will be both outdated and probably inconclusive. Their continued inflexible stand is one that is being rejected by a rapidly increasing number of countries, including the United States, Germany, Italy and the recently formed Global Alliance for the Prevention of Digestive Cancer. Colorectal cancer is the commonest cause of mortality in both non-smoking men and women, with a death from this disease every two hours in Australia. We suggest that introducing screening is far more urgent than Macrae and Hebbard advocate. We re-emphasise the point that individuals should, if they wish, be provided with the opportunity of selecting a screening program from a menu of options chosen after discussion with their primary medical carer.

Terry Bolin · Alistair E Cowen · Melvyn G Korman

Objectives: To investigate whether pantoprazole (20 mg/d) produces significantly greater symptom control than ranitidine (300 mg/d) in patients with gastro-oesophageal reflux disease (GORD).Design: Multicentre, randomised, double-blind, parallel-group comparison.Setting: 76 general practices in north-west Sydney and Newcastle, New South Wales (Australia), from 19 January 1999 to 22 September 2000.Patients: 307 patients aged 18 years or over presenting with symptomatic GORD.Interventions: Pantoprazole (20 mg once daily) or ranitidine (150 mg twice daily).Main outcome measures: Patient-assessed frequency and severity of heartburn using the Gastrointestinal Symptom Rating Scale (GSRS) and a patient heartburn diary.Results: Pantoprazole was associated with significantly higher rates of complete control of GORD symptoms than ranitidine at four weeks (40% v 19%; P < 0.001), eight weeks (55% v 33%; P < 0.001), six months (71% v 56%; P = 0.007) and 12 months (77% v 59%; P = 0.001).Conclusions: Low-dose pantoprazole is an effective alternative to standard-dose ranitidine for initial and maintenance treatment of patients with symptomatic GORD.

Nicholas J Talley MD, FRACP · Michael G Moore FRACGP, GradDipPublicHealth · Arn Sprogis MB BS, FRACGP, GradDipClinEpid · Peter Katelaris MD, FRACP

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

Hepatitis C, other liver disorders and liver health. A practical guide. Geoffrey C Farrell. Sydney: MacLennan and Petty, 2002 ($71.50, xi + 324 pp). ISBN 0 86433 157 6. As this book claims to be aimed at general practitioners and “a broader readership”, including laypeople, I felt that, as a specialist hepatologist, I was not necessarily the best person to review it. I asked a layperson and an experienced general practitioner for their opinions. From the layperson: The book is clearly written and the language and concepts are accessible to a non-medical reader. I particularly liked the style of writing and the tone, which was non-dogmatic when discussing alternative therapies, yet able to convey warnings when necessary. Geoffrey Farrell also shows cultural awareness. The book is easily followed as a reference text. If I had liver disease, I would want to have this book.– Colleen VaughanSecondary School English teacher, Essendon, VIC From the general practitioner: The book is comprehensive and informative. It will answer all your questions — if you can find what you are looking for. Finding information was a problem, as there is so much information packed into the 320 pages. For example, in the chapter “Diet and liver disease — is there a liver cleansing diet?” I had to wade through three recipes, four tables and 18 pages to find the answer — no! I also thought that starting each chapter with case studies, but not presenting the commentaries until the chapter’s end, was confusing. I would have preferred much of the information found in tables and charts to have been placed in appendices so that the book flowed more smoothly.– Robert BensonGeneral Practitioner, Footscray, VIC From the specialist: Does this book add to the cornucopia of print and electronic resources on hepatitis C? Yes, it does! For the health care worker it gives a sensitive, yet scientific, approach to issues which often deeply concern our patients, but are sometimes trivialised by health professionals (eg, diet, complementary therapies). Geoffrey Farrell is courageous enough to debunk the so-called “liver cleansing diet”, even if it did take him 18 pages (see above). On the other hand, the book gives the layperson information on hepatitis C and other liver disorders which is otherwise difficult to access. The style is idiosyncratic and may not appeal to all, but overall it has achieved its goal. It is trustworthy and novel and I’ll be recommending the book both to patients and health professionals. Katrina J R WatsonHepatologist, Fitzroy, VIC

Katrina J R Watson

To the Editor: In Australia, an estimated 11 000 people become infected with hepatitis C virus (HCV) each year.1 Most are injecting drug users. The Early Hepatitis C Intervention Project was a collaboration between the STD Services Surveillance Unit, Drug and Alcohol Resource Unit and Infectious Diseases Unit at the Royal Adelaide Hospital, Adelaide, South Australia. Its objectives were to manage people who had seroconverted in the preceding 12 months and to provide standard treatments for drug use and dependence. Services included information and education on HCV, referral, counselling, psychosocial support and three-monthly clinical evaluation. The project was approved by the Ethics Committee of the Royal Adelaide Hospital and funded by the Department of Human Services for 18 months. The attendance rate was low. Of 88 people with HCV seroconversion who were identified as eligible for enrolment by the Surveillance Unit (from the mandatory notification scheme), 57 agreed to further contact by mail or telephone, and 12 attended for risk assessment. Of these, eight enrolled in the project (10% of those eligible). Despite demographic variation within the group, similarities included difficulties with accommodation, finances, mental health and social integration. Seven of the eight participants had injecting drug use as the risk factor for HCV infection. Most participants also used alcohol and cannabis. During the program, half decreased their risk-taking behaviour: four reduced injecting drug use, and four reduced alcohol use, reaching low risk levels. Characteristics of participants at their last interview are summarised in the Box. Two participants are maintaining regular contact with the Drug and Alcohol Resource Unit. Despite encouragement, few of the target group engaged in the program. We do not know why so few people who agreed to attend a first appointment failed to do so. We did not have their permission or the resources to contact them again. Maintaining contact with participants also proved challenging, and was in part unsuccessful because of complex, multifaceted social issues aside from HCV infection (Box). These included unstable accommodation, use of health services only when in crisis, mental health problems, financial difficulties, polydrug use and continued risk-taking behaviours despite harm-reduction information. In conclusion, the Australian epidemic of HCV infection, driven by injecting drug use, is likely to continue unless a new approach to harm minimisation is developed. Such an approach will recognise that comorbidities and social dislocation influence risk of infection. Unless treatment programs address coexisting problems, it will be futile to offer definitive treatment for HCV infection.2 Within the limited objectives and resources of this project, we were unable to support these people comprehensively. We believe that a "one-stop shop" that includes active and intensive case management by a flexible, multidisciplinary team and deals with social, economic and mental health issues may be a more effective approach to the care of people with recent HCV infection. Characteristics of participants in the Early Hepatitis C Intervention Project at last interview Place of residence Current mental illness* Attendances Age, sex Employ-ment Polydrug use At 5 nominated appointments Total† IDU change‡ Persistent viraemia‡ 19, F No Yes NFA Yes 3 6 Reduced IDU Yes 21, F Part-time Yes NFA Yes 3 5 Reduced IDU No 21, M No Yes NFA Yes 3 4 No IDU at enrolment Yes 24, M Voluntary No Rental Yes 1 1 Denied IDU ever Yes 30, M Casual Yes NFA No 2 4 No IDU Yes 36, M No Yes Parents Yes 1 4 Unknown Yes 38, M Full-time Yes NFA Yes 2 3 Reduced IDU No 43, M Full-time No Rental Unknown 1 1 Unknown No IDU = injecting drug use. NFA = no fixed abode. * Mainly depression, anxiety and personality disorder. † Includes self-initiated visits. ‡ Determined by polymerase chain reaction.

Objective: To determine factors associated with hepatic fibrosis development in people with chronic hepatitis C virus (HCV) infection.Methods: As a requirement for access to interferon therapy through the S100 scheme in Australia, individual pretreatment demographic and clinical information was collected on 2986 patients from 61 hospital-based liver clinics from 1 October 1994 through 31 December 1996. Patients with both a hepatic fibrosis score and an estimated duration of HCV infection (910) were divided into 540 with no or minimal hepatic fibrosis (stage 0–1) and 370 with moderate to severe hepatic fibrosis (stage 2–3). Seven factors were examined: age at HCV infection, sex, ethnicity, source of infection, duration of infection, alcohol intake, and mean ALT level. A further analysis was performed for all 1135 patients with a hepatic fibrosis score disregarding age at and duration of HCV infection.Results: In multivariate analysis, four factors were significantly associated with moderate to severe hepatic fibrosis: age at infection (OR, 2.33 for age 31–40 years, 5.27 for age > 40 years, and 0.20 for age < 15 years, compared with 15–20 years); duration of infection (OR, 1.44 for 11–20 years, 2.74 for 21–30 years, and 8.71 for > 30 years, compared with < 11 years); alcohol intake in previous six months (OR, 1.51 for any intake, compared with none); and mean ALT level (OR, 1.81 for 2–3 times, 2.27 for > 3 times, compared with 1.5–2 times the upper limit of normal). In the analysis disregarding age at HCV infection and duration of HCV infection, older age was strongly associated with moderate to severe hepatic fibrosis (OR, 2.32 for age 36–40 years, 2.46 for age 41–50 years, 7.87 for age 51–60 years, and 7.15 for age > 60 years, compared with 16–30 years). There was no association in either analysis with sex or source of HCV infection.Conclusion: These factors may assist in targeting patients for both liver biopsy-based investigation and therapeutic intervention.

Mark Danta MB BS, MPH · Gregory J Dore BSc, FRACP, MPH, PhD · Yueming Li BSc, MAppStat · John M Kaldor PhD · Chris R Vickers BSc, FRACP · Lisa Hennessy · Robert G Batey MSc(Med), MD, FRACP, FRCP · Hugh Harley FRACP · Meng Ngu MB BS, PhD, FRACP · William Reed FRACP, FRCP · Paul V Desmond FRACP · William Sievert MD, FRACP · Geoff C Farrell MD, FRACP

To the Editor: In November 1999, the National Health and Medical Research Council (NHMRC) released Guidelines for the prevention, early detection and management of colorectal cancer.1 One chapter addressed screening for colorectal cancer (CRC), citing Level 1 evidence in support of faecal occult blood testing (FOBT) as the preferred modality for population-based CRC screening. Colonoscopy and sigmoidoscopy were not recommended. In a postal survey conducted in 1998, before release of these guidelines, we found mixed views among Australian surgeons about CRC screening.2 In February 2001, we conducted a follow-up (post-guidelines) survey which included three questions about CRC screening that had been asked in the pre-guidelines survey. Using a pre–post design, we evaluated the impact of the NHMRC guidelines on surgeons' views. Of the 172 surgeons confirmed still to be in active practice at the time of follow-up, 114 (66%) returned questionnaires. One hundred and three (90%) agreed to matching of their baseline and follow-up responses. Of these, 101 (98%) provided valid responses to each of the three questions on both occasions. Surgeons' views about population-based CRC screening by FOBT changed significantly between the surveys (Box). At baseline, half "strongly agreed" or "agreed" that population-based FOBT should be introduced for all Australians over the age of 50 years. At follow-up, the proportion had increased significantly to more than two-thirds (McNemar's χ2 = 13.0; P < 0.001). There was no significant change in the percentage of surgeons who "strongly agreed" or "agreed" that colonoscopy is preferable to FOBT (McNemar's χ2 = 0.9; P = 0.3). In contrast, there was a significant decrease in the percentage who "strongly agreed" or "agreed" that sigmoidoscopy is preferable to FOBT (McNemar's χ2 = 4.4; P = 0.04). Although the influence of events unrelated to the NHMRC guidelines cannot be entirely excluded from uncontrolled evaluation designs such as this, our data provide some reassurance that the guidelines have had an impact. However, as argued elsewhere,3 substantially more effort is required to ensure that patients with CRC detected through screening receive evidence-based management. More rigorous study designs with control groups are recommended to identify strategies effective in changing surgical practice. Finally, surgeons' increased enthusiasm for CRC screening contrasts with public hesitancy.4 Surgeons' views about screening for colorectal cancer before and after publication of national guidelines1 (n = 101) Strongly agree Agree Neutral Disagree Strongly disagree Population-based screening by FOBT should be introduced for all Australians over 50 years of age Before After 17% 26% 34% 44% 28% 23% 18% 8% 4% 0 Colonoscopy is preferable to FOBT as a population-based screening method Before After 6% 7% 23% 28% 21% 22% 42% 37% 9% 7% Sigmoidoscopy is preferable to FOBT as a population-based screening method Before After 2% 1% 23% 13% 13% 23% 55% 55% 8% 9% FOBT = faecal occult blood testing. Due to rounding, row percentages do not necessarily sum to 100%.

Annie Cooney · Neil J Donnelly · Melina Gattellari · Jeanette E Ward

To the Editor: Hydroxymethylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (or statins) are widely prescribed, and any class-specific side effect has the potential to affect many thousands of patients. The statin drugs are well recognised as a cause of mild and usually transient hepatitis.1-3 Cholestatic liver injury has been reported with simvastatin4 and atorvastatin,5 but pravastatin has only been implicated as a cause in one report.6 We report a 64-year-old woman who was twice treated with pravastatin sodium and who, on both occasions, demonstrated cholestasis, which, at its peak, was associated with minimal hepatocellular injury. Our patient presented to the liver clinic of the John Hunter Hospital in 2001 for investigation of abnormal liver function test results. She was taking diltiazem, aspirin, irbesartan plus hydrochlorothiazide, and pravastatin as therapy for hypertension and hyperlipidaemia. She consumed less than 10 g alcohol per week. Liver function tests showed a predominant elevation of alkaline phosphatase and γ-glutamyltransferase, with a minimal rise in alanine and aspartate aminotransferases, a picture consistent with cholestasis rather than hepatocellular disease (see Box). She had started taking pravastatin in the three months preceding her referral, and commented that when she was taking the drug in the previous year she had also had abnormal liver test results. Her liver function test results in 1998 were normal. Two ultrasound examinations of the liver, performed after five months of taking pravastatin in the first period and two months after beginning her second period of therapy, showed normal liver size and echogenicity, and no sign of obstructive liver disease. Tissue antibodies, viral studies for hepatitis viruses, α1-antitrypsin and iron studies were all either normal or negative. Renal function was normal throughout. She had no biochemical evidence of impaired hepatocellular function, and for this reason liver biopsy and endoscopic retrograde cholangiopancreatography were not undertaken. In view of the association the patient made between previously ceasing therapy with the drug (because she felt unwell) and improving liver function, therapy (which was recommenced by the cardiologist for hyperlipidaemia) was again suspended and within two months liver test results improved markedly. We believe that in the absence of other markers of liver disease and with improvement of liver function on both occasions that therapy with pravastatin was suspended, it is likely that this patient has twice developed a cholestatic response to pravastatin. Patient's liver function test results during and after two periods of pravastatin therapy Initial period Second period* Normal range Pravastatin No pravastatin Pravastatin No pravastatin Test Month 0 Month 4 Month 5 Month 6 Month 10 Month 0 Month 1 Month 2 Month 3 Bilirubin (µmol/L) < 20 7 13 5 7 10 11 11 7 9 Alkaline phosphatase (U/L) < 115 230 362 220 213 242 291 347 186 171 γ-Glutamyltransferase (U/L) < 25 259 625 353 231 195 297 463 167 126 Alanine aminotransferase (U/L) < 40 26 85 31 25 28 25 49 16 18 * Commenced seven months after initial episode. Patient's results were normal two years before the initial period.

Robert G Batey · Michelle Harvey

Plastic bread clips are a rare but potentially avoidable cause of gastrointestinal obstruction or perforation which can be fatal. Case 1: A 79-year-old woman presented with peritonitis thought to be the result of a perforated viscus. Her condition was too poor for immediate operative intervention, and despite supportive treatment she died the same day. At autopsy, ileal perforation was identified related to a firmly adherent plastic bread tag (Figure). Two adjacent foci of congestion and mucosal distortion 24 cm proximally suggested a prior clip attachment site. She had suffered from dementia and her meals were made by her husband, who was blind. Bread tag from the patient in Case 1, detached to reveal the site of ileal perforation. Scale is in centimetres. Case 2: An edentulous 82-year-old woman presented with a one-day history of abdominal pain. A laparotomy showed ileal perforation related to a bread tag attached to the mucosa. Postoperatively, she developed bronchopneumonia which proved fatal. Three months before presentation, she had suffered a less severe episode of abdominal pain which had resolved on conservative treatment from her general practitioner. In Australia most bread bags are sealed by hard plastic clips. These are cheap and convenient, enabling the bag to be resealed after use. However, some countries have withdrawn their use because of gastrointestinal problems after ingestion.1,2 Patients swallowing clips are typically elderly and edentulous. The clips tend to snag on the small bowel mucosa, which may obstruct, erode or perforate. Impaction in the oesophagus, stomach or colon has also been reported.3 The tags are generally not seen on plain x-ray2 and patients are often unaware that they have swallowed them. Because of the high risk of complications, early endoscopic removal is advocated.4 With an ageing population, the proportion of edentulous people is likely to rise, increasing the risk of foreign-body ingestion. Alternative plastic bag sealers are available, although some also present health hazards. For example, ileal perforation has been reported after swallowing a freezer bag tie containing a wire.5 Bread bag clips have recently been replaced with tape in the United Kingdom for safety reasons (A Bennett, Allied Bakeries Customer Services Representative, Allied Technical Centre, Maidenhead, Berkshire, UK, personal communication). Abandoning the use of hard plastic bread tags in Australia in favour of adhesive tape would counter this health hazard.

Trevor W Beer MB ChB, MRCPath

We are making progress in our understanding of the hepatitis C virus, but there is still a long way to go The identification of the hepatitis C virus (HCV) in 19891 delineated a disease previously masquerading under the title of "non-A, non-B hepatitis". In the ensuing years, hepatitis C has become a national epidemic, with more than 150 000 Australians known to be infected. It is estimated that an additional 11 000 new infections occurred each year during the 1990s.2 Escalating rates of HCV infection will have enormous consequences, as 10%–15% of people infected have the potential to progress to end-stage liver disease, with all the implications that has for healthcare services in the years ahead.3 Australia has taken many unique steps in its handling of the hepatitis C epidemic. In 1994 and 1997, the National Health and Medical Research Council published two major reports from working parties comprised of specialists, general practitioners and community representatives.4,5 These were seminal in directing approaches to the diagnosis, treatment and management of HCV-infected people and, to a lesser extent, prevention of further spread. Indeed, Australia was the first country to develop a National Strategy for HCV.6,7 NSW Health has held successful Hepatitis C Awareness Weeks in 2000 and, more recently, in 2002, which have increased public awareness of many issues relating to HCV. NSW Health has recently released a Treatment and Care Plan for HCV, which, among other things, emphasises the importance of GPs in the evaluation and management of HCV-infected people.8 The possibility of accrediting appropriately trained GPs to prescribe anti-viral therapy for HCV is also discussed. So, where are we going? The recent report by the Anti-Discrimination Board of NSW on hepatitis-C-related discrimination presents compelling evidence that there is still much to be done if we as a society are to be seen to be dealing caringly and rationally with this disease.9 The report highlights the disturbing reality that most discriminatory actions against people infected with HCV are perpetrated in healthcare settings. The HCV Projections Working Group of the Australian National Council on AIDS, Hepatitis C and Related Diseases, which advises the federal Minister for Health on these diseases, will report later this year on the increasing rate of HCV acquisition, highlighting the imperative of improving our prevention strategies. The rate of infection is increasing, in large part, because an increasing number of young people are choosing to commence injecting drug use. While public messages on safe injecting practices are promoted widely, many young people ignore these messages in their early phase of drug use. The HCV antibody prevalence rate in those injecting for less than three years fell from 22% in 1995 to 13% in 1997,10 but, despite enormous efforts to increase the availability of clean needles to users, the rate has not dropped any further. Treatment availability and efficacy also remain problematic. Australia offers, through the "highly specialised drugs" program, combination therapy with alpha interferon and ribavirin, providing a sustained viral response rate of 40% overall (ie, in 40% of treated patients, HCV RNA remains undetectable by polymerase chain reaction) (patients with HCV genotype 2 or 3 can expect a 60%–70% sustained response rate).11 By limiting treatment to patients with fibrosis on liver biopsy, the Pharmaceutical Benefits Advisory Committee led, rather than followed, a trend to downplay the need for treatment of all patients. This has highlighted the need for management strategies for those not eligible for, or choosing not to have, treatment. Many major centres now offer support services and education programs, allowing individuals to defer treatment, awaiting better options in the future. Progress is being made in providing better services for prison inmates, among whom there is a high prevalence of HCV infection. In the past, access to therapy has been limited, but the appointment of specialists to Corrections Health services and the funding of a health study of the Tasmanian corrections system is changing that. Prevention strategies are harder to implement. Bleach is made available in most prisons, and methadone programs are expanding, but needle/syringe programs are not available. HCV-infected people from non-English-speaking backgrounds have the added problem of a language barrier. Treatment facilities have become increasingly aware of the need to provide special support for these patients. This is particularly needed if antiviral therapy is to be commenced. What needs to be done better? Greater attention must be directed to reducing spread within the most at-risk community, namely our population of injecting drug users. This group remains marginalised for reasons that are easy to explicate but difficult to overcome. Debate must continue on optimal ways to reduce the risk of young people contracting HCV infection. Needle/syringe programs, while unpopular with many people in our society, have the potential to reduce the risk and must be supported by those who are in a position to influence policy. We need to increase public awareness of the improved efficacy of treatments. We also need to direct more effort towards improving the evaluation and assessment of patients by GPs before referral to busy liver clinics, so that only those who are eligible for and wanting treatment are referred. The HCV research effort requires further support from major funding bodies, and relevant groups are pursuing this actively. A greater understanding of the virus, the mechanisms of viral clearance and the immunopathogenesis of the disease is required urgently. Research is under way to develop a vaccine. In summary, we are some of the way there, and making progress, but there is still a long way to go!

Robert G Batey MD FRACP FRCP

Objective: To determine the prevalence of colorectal neoplasia detected by rescreening people with average risk five years after initial screening by flexible sigmoidoscopy.Design: Prospective survey of results of a colorectal cancer screening program.Participants: People aged 55–64 years with no symptoms or family history of colorectal cancer who were recruited from the community for flexible sigmoidoscopy screening five years previously (July 1995 to December 1996) and had no colorectal neoplasms detected.Setting: Fremantle Hospital, Western Australia, a community-based teaching hospital, December 2000 to June 2001.Main outcome measures: Number and size of colorectal neoplasms (adenomas or cancer) compared between rescreened patients and initial screening population (all 982 people screened between July 1995 and December 1996).Results: 803 people were eligible for rescreening; 138 were no longer at the recorded address, and 361 of the remaining 665 (54%) were rescreened. Rescreening found a significantly lower prevalence of colorectal adenomas than initial screening (8% [95% CI, 5%–11%] versus 14% [95% CI, 13%–15%]; P < 0.05) and also a lower percentage of adenomatous polyps over 5 mm in diameter (32% [95% CI, 15%–49%] versus 51% [95% CI, 46%–56%]; no significant difference).Conclusion: Average-risk people who have been screened for colorectal neoplasms, with none found, have a low prevalence of neoplastic lesions five years later. Longer rescreening intervals need to be considered.

Cameron F E Platell PhD, FRACS · Gillian Philpott EN · John K Olynyk MD, FRACP

To the Editor: I read with interest the recent article by Olynyk's group at Fremantle on the prevalence of coeliac disease in rural Western Australia.1 It is now increasingly realised that coeliac disease is underdiagnosed in adults because it may be clinically silent — but not necessarily asymptomatic. The symptoms, however, may be non-specific and not those traditionally associated with coeliac disease. In a recently reported small study from suburban Melbourne,2 I demonstrated that about 5% of patients (5/97) undergoing gastroscopy had coeliac disease based on small-bowel biopsy results. In only one of the patients was the disease suspected clinically. I have used these figures to argue the case for routine duodenal biopsy at the time of gastroscopy, regardless of the indication. It is important to note that in my study none of the patients presenting with diarrhoea, and only one of six with anaemia, had coeliac disease — so that restricting biopsy to this group would have missed most patients with coeliac disease. Timely diagnosis is important, as symptoms may be alleviated, presymptomatic nutritional deficiencies corrected, and the risk of cancer reduced by instituting a gluten-free diet. People presenting for gastroscopy represent a high-yield group for histological screening for coeliac disease in Australia.

Jeremy Ryan FRACP

In reply: We agree with Ryan that coeliac disease is common in the Australian community, with a prevalence of 1 in 250.1 Furthermore, all individuals positive for antiendomysial antibody who undergo small-bowel biopsy have typical features of coeliac disease.1 Clearly, there is a need to increase awareness relating to coeliac disease and determine appropriate screening strategies for our population. Ryan suggests that patients presenting for upper gastrointestinal endoscopy represent a group in whom a high diagnostic yield of coeliac disease is expected. However, clinical expression of the disease is variable.1 In this setting, we believe that it is important to determine the cost-effectiveness of the various screening strategies before introducing broad-based screening.3 There is no doubt that treatment of symptomatic patients who present with coeliac disease is appropriate, but there are limited data on outcomes for asymptomatic patients who are discovered in population-based screening programs. As we stated in our article, we recommend screening by serology and small-bowel biopsy if the clinical suspicion is high or the patient is in a high-risk group.

John K Olynyk BMedSc, MD, FRACP · Digby J E Cullen MB BS, FRACP · Guy Vautier BM, MRCP · Judith A Collett MB ChB, FRACP · Dominic F Mallon MB BS, FRACP · Chris J Hovell MRCP, DM