Digestive system diseases

The biology of colorectal cancer provides an important opportunity for cancer prevention, as most cancers in the lower bowel evolve from polyps (adenomas). Removal of adenomas markedly reduces the subsequent risk of disease. Consequently, the rational aim of any prevention program should be not only to detect early cancer but also the precursor adenoma. The strategies to reduce mortality include: investigation of high-risk symptoms such as rectal bleeding — often by colonoscopy; colonoscopic surveillance for those with a personal or family history of colorectal cancer or polyps; and screening, beginning at age 50 years, of individuals of average risk, who account for 85% of sporadic cancers. The practice of colorectal cancer prevention in Australia has been largely influenced by recent National Health and Medical Research Council (NHMRC) guidelines.1 An attempt to finalise these guidelines began in 1997 and their slow gestation may have rendered them insensitive to more recent data and not typical of practice worldwide. Three of the major NHMRC recommendations remain controversial. Patients with a single first-degree relative with colorectal cancer diagnosed over the age of 55 do not have a sufficiently increased risk to warrant colonoscopic surveillance. The NHMRC guidelines quote a twofold increase in risk in this group. A recent analysis of 27 case–control and cohort studies indicates that the relative risk is 2.25 and that this risk doubles with more than one relative affected.2 We believe that a doubling of lifetime expected risk of colorectal cancer in men from 1 in 18 to 1 in 9 (only slightly lower in women) is sufficient to advocate colonoscopic surveillance on a five-yearly basis starting at the age of 40, irrespective of the age of the relative. Patients with a single adenoma < 1 cm in size not showing any villous component need colonoscopic follow-up only at 4–6-yearly intervals. This recommendation is mainly based on the US National Polyp Study.3 It is difficult to reconcile these data with other reports. For example, Rex et al3 showed "miss-rates" of 5% for colorectal cancer, and polyp "miss-rates" ranging from 6% to 15%, even in experienced hands. Therefore, there needs to be considerable flexibility in planning postpolypectomy surveillance. Two articles in this issue of the Journal, by

Terry Bolin MD, FRCP · Alistair E Cowen MD, FRACP · Melvyn G Korman PhD, FRACP

Objectives: To assess whether referrals for surveillance colonoscopy and subsequent follow-up recommendations for patients with a family history of colorectal cancer concurred with the published National Health and Medical Research Council (NHMRC) guidelines.Design: A prospective audit of patients with a family history of colorectal cancer referred for surveillance colonoscopy. Follow-up recommendations were assessed retrospectively.Setting and subjects: All patients referred to a major teaching hospital for surveillance colonoscopy on the basis of a family history of colorectal cancer from 2 January 2000 – 15 April 2001.Main outcome measures: Concurrence of referrals and recommendations with NHMRC guidelines.Results: Of 340 patients referred because of a family history of colorectal cancer, 202 (83 men, 119 women) were asymptomatic. Their mean age was 50 years (95% CI, 48.3–51.6 years). The family history of 95 (47%) of these patients satisfied the NHMRC criteria for colonoscopic surveillance. Another 20 patients (17%) satisfied the criteria, but were referred before the recommended age to commence surveillance. Analysis by referral source showed that the proportion of referrals meeting NHMRC guidelines was higher from specialists than from general practitioners (75% v 45%), and this difference was significant. Follow-up recommendations, when made, concurred with NHMRC guidelines in 81% of cases.Conclusions: Further education of the medical community is required to increase understanding of colorectal screening strategies and ensure appropriate resource allocation.

Ian F Yusoff MB BS, FRACP · Neville E Hoffman PhD, FRACP · Hooi C Ee PhD, FRACP

Objectives: To determine whether applying National Health and Medical Research Council (NHMRC) guidelines for colorectal cancer prevention would reduce the number of follow-up colonoscopies.Design: A prospective audit of colonoscopic surveillance decisions before and after the intervention.Setting: The endoscopy suite at a metropolitan tertiary hospital three months before and after January 2000. Intervention: Dissemination of NHMRC guidelines, and supervision of application of the guidelines by a nurse coordinator.Subjects: We compared colonoscopic surveillance decisions before and after the intervention in two groups of 100 consecutive patients after polypectomy and in two groups of 50 consecutive patients with a family history of colorectal cancer after a normal colonoscopy. Main outcome measures: Change in concordance of decisions with NHMRC guidelines; and effect on number of follow-up colonoscopies.Results: After the intervention, the proportion of postpolypectomy surveillance decisions matching the guidelines increased from 37% to 96% (P < 0.05). The mean time to repeat colonoscopy after polypectomy increased from 2.7 to 3.5 years (P < 0.005) (ie, a 23% reduction in the number of postpolypectomy surveillance colonoscopies performed per year). Likewise, the proportion of family-history surveillance decisions matching the guidelines increased from 63% to 96%. Adhering to the guidelines resulted in a 17% reduction in colonoscopies performed on the basis of a family history of colorectal cancer.Conclusions: Supervised application of evidence-based guidelines to a colorectal cancer surveillance program significantly reduces the number of surveillance colonoscopies performed.

Peter A Bampton FRACP · Jayne J Sandford BN · Graeme P Young MD, FRACP

The ability to remain continent is fundamental to our functioning as socially capable individuals. Loss of faecal continence leads to physical, psychological and social disability. Contrary to common belief, the condition is not confined to the disabled elderly. Rather, it affects people of all ages. The greatest contribution to improving the care of people with faecal incontinence would come from improved recognition by doctors. If those who experience faecal incontinence are able to overcome embarrassment, they will seek help from a doctor, usually their general practitioner. To be told that there is nothing to be done (still a common response) is disheartening — and incorrect. In this issue of the Journal (page 54), Kalantar and colleagues have published important data about the prevalence of faecal incontinence in the Australian community.1 They used a postal questionnaire to determine the prevalence of faecal incontinence over the previous 12 months. Incontinence for solid stool occurred in 2% of respondents, and of liquid stool in 9%. These figures are similar to, or somewhat higher than, data published from the USA and Europe over the last 10 years. All recent studies demonstrate that faecal incontinence is common. Current figures are much higher than estimates from the 1980s and earlier, which appear to have markedly underestimated the true prevalence, probably because of the methods of case ascertainment used and the unwillingness of sufferers to disclose the presence of such a stigmatised symptom. In the study by Kalantar et al, men and women were affected in approximately equal proportion. A perineal tear or surgical trauma were identified as associated factors, as were feelings of impaired rectal emptying, loose bowel actions, and a sense of bowel urgency. Only one in eight of those with incontinence had sought medical care. This was despite impaired quality of life and perception of poorer health. In a specialist centre, the commonest cause of faecal incontinence is structural anal sphincter damage associated with childbirth.2 The most important risk factor is instrumental delivery; other risk factors are a large baby, occipito-posterior position, and a long second stage of labour. Anal endosonography, a painless, quick and non-invasive test, has demonstrated that such damage occurs in up to a third of first vaginal deliveries.3 A third of those with damage will have new bowel symptoms after their delivery. The vast majority of these women have not had a recognised third-degree tear. It is therefore perhaps not surprising that 31% of female obstetricians, when asked about their preferred mode of delivery for their first uncomplicated pregnancy, said they would opt for a caesarean section.4 The main reason given was to prevent perineal trauma. The second-commonest cause of incontinence in a specialist referral unit is postsurgical sphincter damage.2 Some patients have anal sphincter damage as an unavoidable consequence of a necessary treatment (eg, in the care of anal fistula). Others sustain irreversible sphincter damage as a consequence of procedures which are now outdated, such as manual dilatation performed for chronic anal fissure, constipation and non-specific anal symptoms. When there is no structural damage present, the commonest cause of faecal incontinence appears to be a degenerative disorder affecting the delicate smooth muscle which keeps the anal canal closed, the internal anal sphincter.2 In patients with congenital anorectal abnormalities, it has only recently been appreciated that, despite corrective surgery in infancy or childhood, impaired continence can persist into adult life.5 Encopresis, often related to behavioural issues, can also severely affect a child's development. In the elderly, many factors can contribute to impaired continence, including co-morbidity, medications, and social circumstances. Faecal impaction is an important factor in some. Patients with a range of primary disorders, such as neurological disease, inflammatory bowel disease, and connective tissue disorders, can experience severe faecal incontinence. For many this hidden symptom causes them the greatest uncertainty and substantially impairs their quality of life. Is it worth making a diagnosis? Can anything useful be done? Emphatically, yes. Many individuals can be helped substantially, often by a combination of careful history taking, examination for sphincter damage or impaction, and correction of predisposing factors. A broad range of therapies have been applied to this condition. Selection of an appropriate therapy, after correcting simple contributory factors, should be based on the aetiology and severity of a patient's incontinence. The least invasive and safest treatments should be used first. Many patients with excessively strong bowel contractions, or sphincter weakness, can have their well-being transformed by a small dose of an antidiarrhoeal medication such as loperamide. This drug is extremely effective and safe in adults. If patients become constipated, the dose can be reduced. Behavioural techniques, such as "biofeedback" (teaching patients to improve sphincter function using physiological feedback, such as anal electromyography or pressure measurement) and sphincter exercises, help about two-thirds of patients, including some with structural sphincter damage.6 Such behavioural techniques are not simply "exercises"; rather, they involve a complex package of care that includes dietary advice, proper use of constipating drugs, teaching patients to resist urgency, decreasing their sense of panic, sphincter training and counselling. Topical pharmacological therapies have radically altered the management of anal fissure, thereby preventing the need for surgical sphincterotomy (one of the causes of incontinence). The first such topical therapy was glyceryl trinitrate (GTN), which lowers anal tone, thereby allowing fissures to heal. Topical GTN is associated with headache in two-thirds of patients, limiting compliance.7 The use of calcium-channel blockers such as diltiazem offers the same therapeutic benefit but without the side effects.8 Injectable botulinum toxin also lowers anal pressure and allows healing. Topical preparations which raise sphincter tone and prevent leakage, such as phenylephrine, are also under development.9 Only a very small proportion of patients require surgical treatment. Sphincter repair for major obstetric structural damage produces a good short term outcome, but the longer-term results are less satisfactory.10 New surgical techniques include: The artificial bowel sphincter (a circular cuff implanted around the anal canal and inflated to maintain sphincter closure).11 Sacral nerve stimulation by means of a fine electrode implanted through a sacral foramen.12 This is connected to a battery to provide continuous low level stimulation, resulting in altered rectal and sphincter motor function. Dynamic graciloplasty. The gracilis muscle is mobilised from the inner thigh and wrapped around the anal canal. Battery stimulation produces muscle contraction, which increases anal pressure.13 This procedure has limited application owing to its complexity and associated morbidity. When all else has failed, a tiny proportion of patients will be well served by a colostomy. Data such as those published in the Journal today should serve to remind doctors that faecal incontinence is a common and treatable condition. A range of treatments is required if patients with different types and severities of incontinence are to be successfully managed. Such a range of expertise is not readily available in many centres. These data should therefore also remind healthcare planners that this is a health issue which requires action in the community, in addition to multiskilled centres of expertise for the minority of patients who need more intense treatment.

Michael A Kamm

Percutaneous liver biopsy, a technique first accredited to Paul Ehrlich over 100 years ago, is still considered an essential component in the management of most liver diseases. However, the revolution in imaging techniques and development of serological investigations means that, at least for certain conditions, biopsy may no longer be necessary. The usual technique for obtaining liver tissue for histological evaluation of diffuse parenchymal liver diseases is percutaneous needle biopsy, which is performed either blind or guided by ultrasound or computed tomography. The attendant mortality ranges from 0.01% to 0.1%,1,2 the major cause of death being intraperitoneal haemorrhage. Controversy still exists over whether guided biopsies can reduce the complication rate and whether an increased diagnostic yield renders them more cost-effective.3,4 To maximise diagnostic yield, it is usual practice to perform liver biopsy with a 14 G or 16 G needle. Increased complications are observed when clinicians perform liver biopsy less frequently5 and when more than three passes are made.6 It is only relatively recently that guidelines have been established for performing liver biopsies on a day-case basis7,8 and these recommend subsequent observation of patients for 6–8 hours, although the majority of complications are apparent within the first three hours. In this issue of the Journal, Pokorny and Waterland (page 67)9 have examined the safety and possible cost benefits of performing liver biopsy in an out-of-hospital radiology clinic. Of 251 patients who underwent liver biopsy with an 18 G needle, 91.2% were discharged at 60 minutes and none were kept for longer than 2 hours 45 minutes. Moderate to severe pain was reported in 3.6% of patients, but no serious complications were observed. While a histological diagnosis was possible for all patients, it is not usual practice to use an 18 G needle for assessment of diffuse parenchymal liver disease, and there are no data regarding the adequacy of the biopsy (as regards number of portal tracts and number of sections). Could the low morbidity of the study simply reflect the use of a small biopsy needle rather than a positive benefit of radiological control? While a cost benefit was suggested when compared with in-hospital, day-case liver biopsies, the method of cost comparison relied upon two discrepant funding models — the Australian Medicare Benefits Schedule (for out-of-hospital biopsy) and DRG-based funding (for in-hospital biopsy). Ideally, actual resource costs should have been derived for each biopsy setting in order to determine an economic advantage. Does this mean that we should be performing all our routine liver biopsies out of hospital? Although the mortality rate after liver biopsy in Pokorny and Waterland's study was low, the study does not have the power to demonstrate a clearly comparable safety profile between out-of-hospital and in-hospital liver biopsy. However, it is unlikely that a formal study with sufficient power will ever be conducted to prove this point, and perhaps ongoing audit of in-hospital and out-of-hospital biopsy and documentation of similar outcomes is all that is required to prove the safety of shorter recovery times and out-of-hospital biopsy. Nonetheless, if a major complication such as haemorrhage did occur, it would require urgent intervention that would be easier to provide in a hospital environment. The American Gastroenterological Association recommends that biopsies be performed in a unit with blood-banking facilities and an approved laboratory.7 Apart from the logistics of where liver biopsy is carried out, there is a major issue of why biopsy should be performed. There are differing opinions on the indications for liver biopsy. Current practice has recently been reviewed2 and the British Society of Gastroenterology has published guidelines for the use of liver biopsy in the United Kingdom.8 A key factor in the decision-making process should be whether knowledge of liver histology is likely to affect patient management. Histological assessment can help either to reach a diagnosis or to grade severity of disease in patients with a known hepatic disorder. Therefore, deciding whom to biopsy can be approached in one of two ways. In patients with a known or suspected disorder, biopsy enables staging of inflammation and fibrosis, providing the clinician and patient with a well-informed and accurate prognosis. This can guide or determine eligibility for treatment regimens and, in patients with cirrhosis, determine whether they should be enrolled in screening programs for hepatocellular carcinoma. The other major role of liver biopsy is in investigating patients with abnormal liver function tests (LFTs) for whom serology and imaging have been unhelpful in reaching a diagnosis. Chronic hepatitis C is probably the most rapidly growing indication for liver biopsy in Australia. Current S100 Pharmaceutical Benefits Scheme regulations require liver biopsy before consideration of treatment of chronic hepatitis C, except in patients for whom liver biopsy is contraindicated. Should liver biopsy be performed routinely in all patients before antiviral treatment, and how does it really benefit the patient? There is growing debate on this issue within Australia10 and overseas,11 indicating that we need to re-evaluate the role of liver biopsy in hepatitis C. The commonest cause of persistently abnormal LFTs (in the absence of markers for infectious, metabolic, autoimmune or hereditary liver disease) is non-alcoholic fatty liver disease. In a study by Daniel et al of 81 marker-negative patients with abnormal LFTs who had liver biopsies, eight patients had normal liver histology, while the remaining 73 patients all had some degree of steatosis.12 Non-alcoholic steatohepatitis was found in 26 of these patients and two had cirrhosis. Although there is a risk of cirrhosis in patients with non-alcoholic steatohepatitis, this is minimal in the absence of diabetes and obesity and in patients under 45 years.13 The result of a biopsy in patients at low risk of cirrhosis is unlikely to influence management and has not been shown to improve the benefit–risk ratio. A final issue relates to who should perform liver biopsy. Clearly, appropriately trained clinicians should do so.5 If out-of-hospital biopsy becomes routine, there will be less opportunity to provide supervised training for registrars in this procedure. Current Gastroenterological Society of Australia guidelines for advanced training recommend that around 50 successful, supervised biopsies be performed to ensure adequate training. So, who should be trained to perform liver biopsy and how do we accredit such individuals? Liver biopsy provides invaluable information and a histological diagnosis remains the gold standard in many liver disorders. However, the benefits for diagnosis and management need to be clearly defined before subjecting patients to an invasive procedure, albeit one with low risk. While the study by Pokorny and Waterland9 tempts us to move to an out-of-hospital, short-stay approach to liver biopsy, the issues of safety and diagnostic adequacy of relatively small core biopsies need to be well proven before this approach can be more widely adopted.

Adrian Griffiths MB BS, MRCP · Charlie H Viiala MB BS · John K Olynyk MD, FRACP

Objective: To determine the prevalence of faecal incontinence in the community and evaluate identifiable risk factors.Design and setting: Cross-sectional survey using a validated questionnaire. A short version of the questionnaire was sent to 220 subjects and a long version to 770 subjects, randomly selected from western Sydney, Australia.Main outcome measures: Self-reported faecal incontinence, defined as involuntary loss of anal sphincteric control leading to unwanted release of liquid or solid faeces (not flatus) at an inappropriate time or in an inappropriate place, within the past 12 months. The long questionnaire also sought information on bowel habit and potential risk factors for faecal incontinence.Results: The response rate was 66%. The prevalence of solid or liquid faecal incontinence was 2% and 9%, respectively. The mean age of subjects with faecal incontinence was 53 years; 55% were women. After adjusting for age and sex, there was a significant association between faecal incontinence and perianal injury (P = 0.03), perianal surgery (P < 0.001), feelings of incomplete defecation (P < 0.0001), loose or watery motions (P < 0.0001) and urgency (P < 0.0001). Seven of 48 subjects with faecal incontinence reported being asked by their physician about faecal incontinence and nine of 33 reported seeking medical advice for their incontinence. Subjects with faecal incontinence perceived their health to be significantly poorer than did other subjects (P = 0.02).Conclusion: There is a high burden of faecal incontinence in the community, and the prevalence in men may be greater than is usually appreciated. Despite significant associated morbidity, most cases of faecal incontinence were unrecognised by doctors.

Jamshid S Kalantar MB BS, FRACP · Stuart Howell BA(Hons) · Nicholas J Talley MD, PhD

Objective: To evaluate the safety, the quality and adequacy of specimens obtained and the cost benefits associated with performing liver biopsy out of hospital, on a short-stay basis, using radiological guidance.Design and setting: A prospective study undertaken over a three-year period, from March 1998 to March 2001, in a private radiology practice.Patients and procedures: 251 patients (159 men) with stable liver disease participated. Coagulation studies were performed within a two-week period before biopsy, which was carried out under the guidance of ultrasound (143 patients) or computed tomography (108 patients). A disposable, spring-loaded gun with an 18-gauge biopsy needle was used in each case. A repeat ultrasound or CT scan was performed after the procedure to monitor for complications such as haemorrhage.Main outcome measures: Complications of liver biopsy; adequacy of specimens for histological examination; cost of out-of-hospital procedures compared with liver biopsies performed in the hospital setting.Results: Two hundred and twenty nine patients (91.2%) were discharged 60 minutes after the biopsy. The only post-biopsy complication was pain, either at the biopsy site or in the right shoulder. Pain was severe in three patients and, for one of these patients, a subcapsular hepatic haematoma was found on ultrasound eight days after the biopsy. Sufficient material for histopathological examination was obtained from all patients. The cost of out-of-hospital biopsies was substantially less than the cost of hospital-based, day-stay procedures.Conclusions: Short-stay, out-of-hospital, radiologically guided liver biopsy is safe for patients who have stable chronic liver disease and acceptable coagulation profiles.

Christopher S Pokorny MB BS, FRACP · Mark Waterland MB BS, FRANZCR

Progress in new diagnostic tools and therapeutic strategies has been rapid in gastroenterology and hepatology, and pending advances include the use of magnification endoscopy with dye spraying to detect early cancers, and endoscopic sewing procedures for reflux oesophagitis. Prevention. Genetic tests have recently been developed for the hereditary colon cancer syndromes (< 3% of all colon cancers). This major advance helps to identify at-risk family members, so that premalignant lesions and early cancers can be removed, and those who are not carrying the gene can be reassured. Accuracy in both familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) approaches 100%, as long as the index case is positive for the mutation tested. The rate of carriage of an easily identifiable mutation is about 80% in FAP, but presently substantially less in HNPCC.1 Pilot testing of population screening for common (sporadic) colorectal cancer is about to begin in Australia. More specific immunochemical tests for occult gastrointestinal bleeding are now available. Diagnosis. First described in 1991, magnetic resonance cholangiopancreatography (MRCP) continues to evolve. It produces diagnostic-quality images of normal and diseased biliary ducts, is non-invasive, and does not require contrast media or ionising radiation. MRCP is gradually replacing invasive techniques, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography, for purely diagnostic imaging, leaving these procedures for interventional or problem cases. MRCP is indicated for detecting biliary stenosis and level of obstruction, and depicting the biliary tree on both sides of the stricture. It is also useful in identifying cases of choledocholithiasis likely to benefit from ERCP calculus removal. Avoiding intubation of the biliary tree decreases the risk of bacterial colonisation in cases of biliary stricture (including primary sclerosing cholangitis [PSC]) and choledocholithiasis. MRCP is not particularly good for detecting ampullary calculi, or assessing chronic pancreatitis or the very early changes of PSC. Availability is the main limiting factor to its widespread use.2 Intervention. Localised hepatocellular carcinoma (HCC) in patients with non-cirrhotic livers is best managed by surgical resection. Liver transplantation has been associated with excellent long term survival in highly selected cases of cirrhosis, but is limited in Australia by a small donor pool. Effective local control of small HCCs has been achieved with percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA). The main determinant of outcome is the size of the tumour. PEI, under ultrasound or computed tomography guidance, is simple, inexpensive and safe in patients with advanced cirrhosis. It is suitable for HCCs less than 3 cm in size, with fewer than three nodules, but multiple treatments may be required. There is minimal discomfort, so it can be performed as an outpatient procedure. RFA involves placing the needle electrode percutaneously with laparoscopic control or ultrasound guidance under local anaesthesia. However, heavy sedation or anaesthesia may be required as significant pain may occur. Both PEI and RFA have very low complication rates, and treatment can be repeated for recurrence or new lesions. Long-term survival rates have been reported at over 70% (three years) and over 40% (five years), but unfortunately no randomised controlled trials have been performed.3 The management of chronic hepatitis B infection has changed recently with approval of lamivudine, a nucleoside analogue and potent inhibitor of viral DNA replication. Sustained viral inhibition is seen within four weeks in over 95% of cases, with 15%–20% becoming e-antigen negative at 12 months. There is also evidence that liver fibrosis and inflammation decrease during therapy, even without seroconversion. A high proportion of patients with hepatitis B e-antigen seroconversion (73%) have a sustained virological remission for up to 19 months (median). As with other therapies, loss of surface antigen is relatively uncommon. The development of a drug-resistant mutant form of the virus (YMDD) emerges with prolonged therapy (about 50% at three years), and can be associated with significant flares of hepatitis.4 Infliximab, a cytokine-directed biological therapy, represents a significant advance in the understanding of Crohn's disease. This chimeric monoclonal antibody blocks tumour necrosis factor α (ΤΝF-α), a key cytokine in bowel inflammation. Therapy results in rapid reduction in the signs and symptoms of Crohn's disease in two-thirds of cases, with a decrease in bowel inflammation, and improved mucosal healing and quality of life. Three infusions are given for fistulous disease and rapid closure occurs usually within two weeks, with a median benefit exceeding three months. Serious adverse events are infrequent and have been successfully managed with medications. However, the cost of this therapy currently restricts widespread use. Allergic reactions are also a serious consideration, but may be addressed in the future with modified molecules already in trial.5

Amanda J Nicoll PhD, FRACP · Ian J Kronborg FRACP · Neville D Yeomans MD, FRACP

Gastrointestinal surgery continues to be informed by advances in basic science, technology and by the changing expectations of consumers. Prevention. The high rate of adhesions found after abdominal surgery supports the need to tackle this problem.1 Options currently being canvassed include simple technical modifications (eg, using powderless gloves), agents that minimise adherence of mesothelial surfaces, and a range of physical barriers that can separate these surfaces. The emergence of Level 1 evidence that mortality can be reduced by screening for colorectal cancer has led to increasing calls for screening programs;2 mooted pilot programs within Australia may herald their future widespread introduction. Prophylactic colectomy is well established for rare inherited colorectal cancer syndromes. Advances in molecular biology are extending this concept to patients with other inherited predispositions to cancer, with potential for broader application within the gastrointestinal tract (eg, gastric cancer).3 Diagnosis. Technological advances have allowed laparoscopy to spearhead advances in diagnosis and treatment. Leaps in imaging techniques (such as video capsules which can be swallowed by the patient, virtual endoscopy, enteroscopy) are enhancing the array of diagnostic tools. The intraoperative use of ultrasound has allowed more accurate staging of cancers and has facilitated hepatic resections. The use of transrectal imaging (ultrasonography, helical computed tomography and magnetic resonance imaging) has similarly assisted decision making and treatment for patients with complex anorectal diseases such as fistulas, abscesses and cancer. Molecular analyses of body fluids (including faeces) may have an increasing role to play in screening and surveillance. Intervention. Laparoscopic surgical management of disorders of the entire gastrointestinal and hepato-pancreatico-biliary tracts is thought to represent a significant advance by many. These and other technology-based advances are tempered by the aphorism that "technology moves faster than knowledge, which, in turn, moves faster than wisdom".4 The removal of rectal cancers by transanal endoscopic microsurgery (TEM) is becoming increasingly common outside Europe, where the procedure was initiated. Further evidence on cancer recurrence and survival when TEM is employed is awaited. A growing evidence base has bolstered adjuvant chemotherapy and radiotherapy treatments,2 and the preoperative use of adjuvant therapy for patients with rectal cancer will allow for down-staging of tumours, giving patients a more favourable prognosis. This may increase further the number of patients amenable to TEM. A similar acronym (TME) represents total mesorectal excision (excision of the perirectal tissue contained within the endopelvic visceral fascia and extending the length of the rectum) when resecting a rectal cancer. Proposed by some with messianic zeal (as reflected by the term "holy plane", which is a guide to the resection), it has been increasingly adopted, despite still-debated benefits in terms of survival and the prevention of local recurrence. Robotic surgery understandably receives much publicity. Surgery from a remote location is unlikely to be adopted widely in the next five years. However, telemonitoring (observation of performance), the use of computers for measuring and guiding dexterity enhancement and for simulating virtual environments are already occurring in multiple skills laboratory training centres.5 A less glamorous (but more painful) surgical topic is the management of patients with an anal fissure. Novel non-surgical interventions (such as the use of glyceryl trinitrate and botulinum toxin) have been described to avoid lateral sphincterotomy, which may cause postoperative incontinence. Quality and communication. Underpinning these advances is the need for surgeons to maintain their competence and to practise according to best evidence, as facilitated by the establishment of the Australian Safety and Efficacy Register for New Interventional Procedures – Surgical <http://www.surgeons.org/asernip-s/publications2.htm>. Doctors must now assiduously inform patients and relatives of benefits and risks of operations. This implies a detailed knowledge of outcomes, as gleaned from clinical-audit and peer-review processes using personal and comparative data. An example of how to collate these data can be found at http://www.pamuk.co.uk. Finally, advances should not be seen in terms of technology alone; knowing what to do and how to do it must be complemented by knowing how to explain what should be done and when and in whom to do it. The two websites cited above are important to facilitate this process.

Allan D Spigelman MB BS, MD, FRACS, FRCS · Daniel R McGrath MB BCh, BAO, MRCS · Richard D Levy MB BCH, DCHSA, FCSSA, FRCS(Edinburgh) FRCS(Glasgow)

Asylum seekers and healthcare Screening for conditions of public health importance in people arriving in Australia by boat without authority Kathleen King and Peter Vodicka MJA 2001; 175: 600-602 Abstract - Methods - Results - Discussion - References - Authors' details - - More articles on Psychiatry Abstract Objective: To determine the prevalence of tuberculosis, hepatitis B carriage and markers of hepatitis C and HIV infection in people detained in immigration reception and processing centres in Australia. Design and setting: Eighteen-month survey of medical conditions of public health importance in people detained at the immigration reception and processing centres at Curtin and Port Hedland in Western Australia and Woomera in South Australia. Participants: 7000 detainees (5742 adults and 1258 children and teenagers aged < 18 years) between 1 January 2000 and 30 June 2001. Main outcome measures: People treated for active tuberculosis; issuing of health undertakings to report to a chest clinic for follow-up of inactive tuberculosis; and confirmation of hepatitis B carrier status or hepatitis C or HIV infection. Results: Eleven people required treatment for tuberculosis (in nine the diagnosis was confirmed bacteriologically), representing a prevalence of 157 cases per 100 000 population. This rate is much higher than the incidence in Australia in 1998 of 4.93 cases per 100 000 population, but comparable with rates in the source countries. Health undertakings were issued to 973 people (13.9%). Of these, 682 (70.1%) were for inactive tuberculosis (26 in association with hepatitis B carriage [16] or hepatitis C infection [10]); and 156, 58 and two health undertakings were for hepatitis B carriage, and hepatitis C and HIV infection, respectively. Conclusions: The health-screening program at immigration reception and processing centres detects significant numbers of conditions of public health importance, enabling treatment and surveillance to the benefit of the people detained and the Australian community. People arriving in Australia by boat without authority are admitted to an immigration reception and processing centre (also known as a "detention centre"), and undergo a protocol-based health assessment. The protocol for entry health assessments at these Department of Immigration and Multicultural Affairs (DIMA) detention centres was devised by a committee with representatives of the Commonwealth Department of Health and Aged Care, DIMA and State and Territory health authorities. The health assessments are concerned with conditions of public health importance only, and identify the minimal health requirements and vaccinations necessary to protect the health of the people detained and the Australian public. The day-to-day healthcare and continuing medical treatment of the people detained are the responsibility of Australasian Correctional Management (ACM), the company that operates and manages DIMA's detention centres. All people detained are given medical examinations to satisfy the requirements for visa application. This examination is used for granting visas in those who are assessed as engaging Australia's obligations for protection under the United Nations Convention relating to refugees. By the time that this assessment is complete and the people are released from detention, they will have completed the full, formal medical examination for the granting of a temporary protection visa.1 An onshore protection visa can be granted even when a medical condition is present. We describe the conditions of public health importance noted in the health assessment process for the possible granting of visas (Box 1; the tinted entries indicate the health examinations included in our study). Methods Our report includes all people receiving medical screening in the immigration reception and processing centres at Curtin and Port Hedland in Western Australia and Woomera in South Australia between 1 January 2000 and 30 June 2001. Chest x-ray examinations were performed at Derby Base Hospital, at Port Hedland Hospital and at Woomera Base Hospital, and x-ray films were read either by chest-clinic physicians or by private radiologists, or both. Medical examinations for granting of visas were performed by medical advisers or approved medical practitioners of Health Services Australia (a government business enterprise contracted to DIMA to provide health assessments). People suspected on clinical or radiological grounds of having tuberculosis underwent full evaluation by sputum-smear and sputum-culture tests. Personnel of State chest clinics were kept informed of all cases of suspected tuberculosis and were involved in the management of all people treated for the disease. Specimens, including Mycobacterium tuberculosis isolates, were sent for testing to laboratories in the respective capital cities (Adelaide and Perth). Sensitivity testing was to World Health Organization reference standards and included tests to rifampicin, isoniazid, ethambutol and streptomycin, with an indirect test for pyrazinamide. Serological testing for hepatitis B surface antigen (HBsAg) and hepatitis C and HIV infection was by standard methods. People with non-communicable diseases, such as cardiomegaly or diabetes, identified by chest x-ray or during the medical examinations were referred to doctors employed by ACM for appropriate investigation and treatment. Likewise, people with evidence of sexually transmitted diseases were also referred to ACM doctors for treatment. All subjects gave their consent to examination and data collection for health assessment purposes. Results In the 18-month period, 7000 people were examined in the three immigration reception and processing centres for the possible granting of a protection visa. There were 5742 adults and 1258 children and teenagers (< 18 years of age) (5916 males and 1084 females). The reported citizenship breakdown was 48% Iraqi, 42% Afghani and 4% Iranian, with the remainder being Sri Lankan, Pakistani, Syrian, Turkish and Palestinian. Seven men and one woman were diagnosed with culture-positive, fully sensitive, pulmonary tuberculosis and treated for infection. Except for one man aged 68 years, all those with active tuberculosis were between 17 and 35 years of age, with five being under 23 years. A 21-year-old man with an abnormal chest x-ray film was found to have peritoneal tuberculosis. Two other men, both 34 years of age, had radiological and clinical indications of active pulmonary disease and consequently were treated for tuberculosis. Both had very abnormal chest x-ray films; one also had an enlarged cervical lymph node and the other had a strongly positive Mantoux reaction (27 mm). Thus, the prevalence of active tuberculosis in this population was 157 cases per 100 000. HIV infection was diagnosed in two people. In two others the test results were indeterminate. In one of those with indeterminate results, a subsequently performed polymerase chain reaction test gave negative results and he is thought not to have HIV infection. In total, 973 people were issued with health undertakings should a visa be granted, with 682 being undertakings to report to a chest clinic for further follow-up of inactive tuberculosis (Box 2). Other communicable conditions diagnosed and treated that do not require a health undertaking include malaria (average, one case per 200 arrivals), chickenpox and other childhood infectious diseases, scabies, headlice, and one case of cutaneous leishmaniasis. Detainees also consult the doctors employed by ACM for treatment of routine infections, most commonly skin conditions (eczema, impetigo and fungal infections), respiratory tract infections, and urinary symptoms. Discussion The medical screening program at the immigration reception and processing centres has resulted in the detection of a considerable burden of disease of public health importance. In Australia, cases of tuberculosis are generally diagnosed soon after the disease becomes active, so that the incidence and prevalence are similar. It is not strictly correct to compare prevalence with incidence. Nevertheless, to provide some comparison, the rate of active tuberculosis of 157 cases per 100 000 population found in our study is significantly higher than the reported incidence of tuberculosis in Australia in 1998 of 4.93 cases per 100 000 population.2 The case-notification rates of tuberculosis in the principal source countries of our study subjects — Afghanistan, Iraq and Iran — in 1999 were 15 cases per 100 000 population, 142 cases per 100 000 population and 18 cases per 100 000 population, respectively.3 The first and last rates are likely not to represent true incidences in those countries. For example, in 1991, Afghanistan reported a rate of 148.9 cases per 100 000 population. Thus, the prevalence of tuberculosis in the detention population is a reflection of its prevalence in the source countries. Both for treating the people detained and protecting the Australian community, it is important to screen for active tuberculosis among people in detention centres. As would be expected, the prevalence of currently inactive tuberculosis is also high in this population. One of the strategies used for the control and surveillance of tuberculosis is the issuing of health undertakings to visa applicants with tuberculosis or abnormal chest x-ray films. The applicant signs an agreement to report to a State or Territory government chest clinic for follow-up within a specified period should a visa be granted. Health undertakings to present to a chest clinic for follow-up and surveillance of inactive tuberculosis were required in 9.7% (682/7000) of people, while, of the total group, 13.9% required health undertakings for tuberculosis or other conditions. This proportion is similar to that of overseas visa applicants (14%) who were considered by the Health Assessment Service in 2000-2001 to require health undertakings (unpublished data). In 1995, visa holders' initial compliance rate with health undertakings was 58% overall.4 Changes to the undertakings system foreshadowed in that report have resulted in higher initial compliance rates of around 70% (unpublished data). The tracing system in case of default, also introduced in 1995, has increased final compliance rates to around 75%. State and Territory chest clinics have indicated that compliance rates by people holding temporary protection visas with health undertakings are similar to those of the general population of visa holders with health undertakings. Procedural changes have recently been introduced to require holders of temporary protection visas to notify DIMA of their current addresses and this should further increase compliance with health undertakings. Hepatitis B carriage occurred in 2.5% (172/7000) of the population examined. This rate is at the lower end of the expected rate, as most of the people detained come from countries where the prevalence of HBsAg carriage ranges from 2% to 7%.5 The prevalence of HBsAg carriage in Australia is less than 2%.5 Hepatitis C infection occurred in 1.0% (68/7000) of the population examined. It is also likely that this is a lower rate of infection than might be expected, but there are no data for prevalences of antibody to hepatitis C in Iraq, Iran and Afghanistan.6 In Australia, the prevalence of hepatitis C infection is less than 1%.6 It is important that people with HBsAg carriage and hepatitis C infection are followed up in the Australian health system and counselled appropriately. HIV infection was confirmed in two people, giving a prevalence of 0.03%. This rate compares with estimated prevalences of 0.15% for Australia and of less than 0.01% for Iraq, Iran and Afghanistan.7 Overall, the health-screening program at the immigration reception and processing centres detects significant numbers of conditions of public health importance, enabling treatment and surveillance to the benefit of the people detained and the Australian community. References Department of Immigration and Multicultural Affairs. Guidelines for medical and radiological examination of applicants for onshore protection visas. Canberra: DIMA, 2000. National TB Advisory Committee for the Communicable Diseases Network Australia and New Zealand. Tuberculosis notifications in Australia, 1998. Commun Dis Intell 2001; 25: 1-8. World Health Organization. Global tuberculosis control. WHO report 2001. Geneva: WHO, 2001. King K, Dorner RI, Hackett BJ, Berry G. Are health undertakings effective in the follow-up of migrants for tuberculosis? Med J Aust 1995; 163: 407-411. National Center for Infectious Diseases, Centers for Disease Control. Geographic distribution of chronic HBV infection [modified June 1, 2001]. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/ hep_b/slide_9.htm (accessed July 2001). World Health Organization. Hepatitis C: global prevalence (update). Wkly Epidemiol Rec 2000; 75: 3. UNAIDS/World Health Organization. Epidemiological fact sheets on HIV/AIDS and sexually transmitted infections. 2000 Update (revised). Available at: <http://www.who.int/emc-hiv/fact_sheets/All_countries.html> (accessed October 2001). Authors' details Department of Immigration and Multicultural Affairs, Sydney, NSW. Kathleen King, MB ChB, FRCPath, Director, Special Health Projects. Peter Vodicka, MB BS, DPH, Director, Health Assessment Service. Reprints will not be available from the authors. Correspondence: Dr K King, Department of Immigration and Multicultural Affairs, GPO Box 9984, Sydney, NSW 2001. kathy.kingATimmi.gov.au Make a comment 1: Medical screening services for people coming to Australia by boat without authority Service Type of service/target population When performed Primary purpose* Examiner Initial triage Initial medical examination On arrival/en route To ensure no immediate medical problems ACM nurse and/or doctor Initial medical examination More detailed medical examination including psychological questionnaire and urinalysis Screening for infectious diseases, if indicated clinically Within a few days of arrival at an immigration reception and processing centre To identify medical history and concerns ACM nurse and/or doctor Malarial screening Those coming from or transiting a malaria-endemic country and/or pregnant If presenting with febrile illness or fever in 1st week To identify public health risks ACM Vaccination Children All children Commences within 1 week of arrival Disease prevention ACM Adults If indicated clinically (eg, spouse with hepatitis B infection) When indicated Disease prevention ACM Tuberculosis screening Chest x-ray and medical examination, 12 years or over or symptomatic Mantoux test, Monitoring for pregnant women Within 2 weeks of arrival To identify public health risks ACM Blood screening Test for HIV and hepatitis B and C, ≥ 15 years Within 2 weeks of arrival Required for granting a visa ACM Continuing medical treatment Day-to-day care Referral to specialists Medical tests as required While in detention Continuing care ACM Medical assessment for granting a visa Complete visa medical examination Consider radiological and pathology test results Before granting a visa Required for granting a visa Health Services Australia Release arrangements Where MOC from DIMA's health assessment service has determined that a health undertaking is required Before granting a visa Required for granting a visa ACM + DIMA case officers Tinted entries indicate the health examinations included in our study. ACM = Australasian Correctional Management. DIMA = Department of Immigration and Multicultural Affairs. MOC = Medical Officer of the Commonwealth. *Additional reasons may exist for conducting medical screening and tests. The results of medical and chest x-ray examinations and pathology tests obtained for health management during detention are made available to Health Services Australia for visa requirements. The results of blood tests obtained to satisfy visa requirements are made available to ACM for health management during detention. Back to text 2: Reasons for issuing a health undertaking Reason Number issued Inactive tuberculosis only* Inactive tuberculosis with hepatitis B carriage or hepatitis C infection Pregnancy† Hepatitis B (HBsAg) carriage Hepatitis C infection HIV‡ Other§ 656 26 45 156 58 4‡ 28 * Includes 57 children under 12 years of age referred for prophylaxis with isoniazid. † Pregnant women who did not undergo radiological examination, and showed no clinical evidence of tuberculosis, but will have a chest x-ray examination after confinement. ‡ Includes two cases with indeterminate results. § Includes typhoid (six cases); paratyphoid (two cases); other gastrointestinal diseases (eg, giardiasis); and sexually transmitted diseases (eg, syphilis, gonorrhoea and chlamydial infection) requiring follow-up. Back to text

Kathleen King · Peter Vodicka

Editorial Adult living donor liver transplantation: another Pandora's box? Important issues of safety and consent must be addressed MJA 2001; 175: 179-180 In 1990, the world's first successful living donor liver transplantation, from a mother to her child, was performed in Brisbane.1 Over the past three years, living donor liver transplantation has taken off in both the United States and Europe.2 In this issue of the Journal, House and colleagues from Western Australia report the first adult-to-adult living donor liver transplantation in Australia.3 This report is worthy of comment because it raises questions as to whether this procedure should be widely adopted in Australia, whether donor safety issues have been adequately addressed, and whether adult-to-adult living donor liver transplantation should be monitored and regulated in Australia. The upsurge of adult-to-adult living donor liver transplantation in the US and Europe reflects pressures from a mismatch between the demand for liver transplantation and the availability of cadaveric donor organs. In the US, there is a waiting list for liver transplantation of more than 14 000 patients, and a transplantation rate between 4000 and 5000 per year.4 The situation in the US is aggravated by an organ allocation system which gives priority to time on the waiting list for non-urgent cases: a patient entering the waiting list "late" is likely to receive a transplant only when there is deterioration to a more urgent category. In this system, deaths of patients while waiting for a transplant have dramatically increased over the past few years (in the US, about 1800 in 1999).4 The availability of living donor liver transplantation in an elective setting would presumably reduce or minimise these tragedies by increasing supply to match demand. This situation is not likely to apply in Australia because, although deaths on the waiting list have risen in the past few years, cases can be prioritised without the need to take time on the waiting list into consideration. Furthermore, in Australia, as in the US, patients with acute liver failure have a national priority listing that potentially minimises death while waiting for a suitable cadaveric donor. Nevertheless, the case report by House et al indicates that some of our liver transplantation units wish to introduce this procedure as an option. Hence, there is a need to address some important issues. What are the indications for adult-to-adult living donor liver transplantation? In Australia and New Zealand, it has been agreed to offer adult-to-adult living donor liver transplantation only to patients who have already fulfilled the criteria for a cadaveric donation. In the US and Europe, there is also general agreement on this, although some individual units feel that this is too restrictive and perform adult-to-adult living donor liver transplantation on patients who do not fulfil current criteria for liver transplantation, such as patients with large hepatocellular cancers or with acute alcoholic hepatitis. We believe that this is inappropriate; it is nonsensical to argue for the introduction of adult-to-adult living donor liver transplantation to address the supply-demand imbalance and simultaneously expand recipient criteria to increase demand. How are donors selected? Donor selection clearly requires an agreed formal informed consent process.5,6 The potential donor should be prepared by a team independent of the team advising and caring for the liver transplant recipient. Input from liaison psychiatrists is crucial. Any hint of coercion should lead to automatic exclusion, with the donor team having the final veto for progressing with adult-to-adult living donor liver transplantation. Potential donors should be selected using criteria that include psychological stability, appropriate vascular and biliary anatomy, age, and absence of underlying systemic or liver disease (eg, donation is contraindicated in an obese subject who is a smoker). A donor should be required to have a major emotional link to the recipient and should not be under any financial indebtedness to the recipient. A donor will usually, but not necessarily, be a close family member. A "cooling off" period after donor consent is also recommended. Size-matching of donor and recipient is crucial, since "shortchanging" of functioning hepatic mass in either may be fatal. In Australia, this would generally mean that the donation of an adult right hemiliver is required, although in Japan the left liver volume is often sufficient.7-9 What is the donor morbidity and mortality with adult-to-adult living donor liver transplantation? More than 1000 living donor liver transplantations have been performed worldwide with at least four deaths, although a report of only one has been published.4 Significant biliary complications have occurred in up to 5% of donors, and 2%-3% have required more than one surgical procedure. The donor is usually unable to work for 2-3 months, and 70% have persisting symptoms at six-month follow-up.10 Most living donor liver transplantations have been performed between adults and children, and those between adults include a large number of left liver grafts. This means that the true incidence of morbidity and mortality for right liver grafts remains unresolved. One would expect it to be higher for technical and other reasons related to hepatic mass. What are the outcomes for the recipient? The survival outcomes for recipients of adult-to-adult living donor liver transplantation are the same as with cadaveric donation, although biliary and vascular complications are increased.4 In the case reported by House et al, the patient met the listing criteria for liver transplantation and was on the urgent Australian and New Zealand list for the first available suitable cadaveric donation. The donor was prepared by an independent team in a process that took five days. The outcomes were favourable for both recipient and donor, although the follow-up of the donor is short and the recipient has already had significant biliary complications. However, the use of adult-to-adult living donor liver transplantation for fulminant hepatic failure requires comment. There is an Australasian priority listing for such patients. In the US, such a priority listing has usually obviated the need for adult-to-adult living donor liver transplantation.11 In Australia and New Zealand, waiting list deaths for fulminant hepatic failure are high, in the order of 30%. In Western Australia, the rate is 60%; the reason for this is unclear. Furthermore, in many patients with fulminant hepatic failure, for whom transplantation may be required within 24-72 hours of presentation, a donor consent "cooling off" period may not be possible. In the reported case, five days passed without a cadaveric donor, allowing such fears to be allayed. In many cases, this may not be so. In the US, it has been estimated that 600 transplantations per year may be possible with the widespread introduction of adult-to-adult living donor liver transplantation.4 If this figure is extrapolated to Australia and New Zealand, then between 20 and 30 cases can be expected each year. This amounts to only 1-15 cases in each Australian unit. Is this enough to justify widespread adoption of this procedure? Probably not. A recent commentary suggests that adult-to-adult living donor liver transplantation be restricted to "high case load" institutions,12 and states: The rapid proliferation of programmes that perform (liver) transplantation in adults with the use of grafts from living donors (most of those in the United States have performed fewer than 10 procedures each) is alarming for an innovative, nonstandardised operation that places two people, one of whom is healthy, at risk. It is clear there is a significant learning curve, with higher morbidity in donors and increased complications in recipients at units that have performed fewer than 50 adult-to-adult living donor liver transplantation procedures.4 Perhaps a single Australian centre should be established to do these procedures in the elective setting, although this may be logistically difficult to achieve. What is certainly achievable, however, is an agreed Australian and New Zealand protocol for donor and recipient selection, together with a central registry of transplantations performed. The Transplant Society of Australia and New Zealand is currently undertaking this process with the support of all liver transplantation units. The resulting protocol will be placed in the public arena for comment. Similarly, the Australian Safety and Efficacy Registry of New Interventional Procedures (Royal Australasian College of Surgeons) is undertaking a review of the need for adult-to-adult living donor liver transplantation in Australia. House and colleagues are to be recognised for their courage and ethical and technical skill in performing this procedure in a life-or-death situation. However, only time will tell whether this Pandora's box, containing within it all the issues of adult-to-adult living donor liver transplantation, should have stayed shut.13 Geoffrey W McCaughan A W Morrow Professor of Medicine, and Director Australian National Liver Transplantation Unit Royal Prince Alfred Hospital, Sydney, NSW Stephen V Lynch Associate Professor of Surgery, and Director, Queensland Liver Transplantation Unit Princess Alexandra Hospital, Brisbane, QLD Strong RW, Lynch SV, Ong TN, et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 322: 1505-1507. Renz JF, Busuttil RW. Adult-to-adult living-donor liver transplantation: a critical analysis. Sem Liver Dis 2000; 20: 411-424. House AK, Jeffrey GP, Edyvane KA, et al. Adult-to-adult living donor liver transplantation for fulminant hepatic failure. Med J Aust 2001; 175: 202-204. Proceedings of the 2nd international symposium dedicated to expand the donor pool. Rome. 26 August 2000. Tokyo: CD Toppon Medical Science, 2000. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000; 284: 2919-2926. American Society of Transplant Surgeons' position paper on adult-to-adult living donor liver transplantation. Liver Transpl 2000; 6: 815-817. Yamaoka Y, Morimoto T, Inamoto T, et al. Safety of the donor in living-related liver transplantation — an analysis of 100 parental donors. Transplantation 1995; 59: 224-226. Marcos A. Right lobe living donor transplantation: a review. Liver Transpl 2000; 6: 3-20. Fan S, Lo C, Liu C, et al. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000; 135: 336-340. Trotter J, Talamantes M, McClure M, et al. Right hepatic lobe donation for living donor liver transplantation: impact on donor quality of life. Liver Transpl 2001; 7: 485-493. Hymar A, Durand B, Knaak M, et al. Sharing of livers for status I recipients in Region 7 — A good thing. Am J Transpl 2001; 1 Suppl I: 283 (A587). Cronin DC, Millis JM, Siegler M. Transplantation of liver grafts from living donors into adults — too much, too soon. N Engl J Med 2001; 344: 1633-1637. Strong RW. Whither living donor liver transplantation? Liver Transpl Surg 1999; 5: 536-538. Make a comment Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company.

Notable Cases Adult-to-adult living donor liver transplantation for fulminant hepatic failure The outcome of fulminant hepatic failure without timely liver transplantation is poor. We describe a 19-year-old woman with fulminant hepatic failure due to acute hepatitis B infection who received a living donor liver transplant from her sister. The donor's recovery was uneventful, allowing hospital discharge on Day 6. Two months after transplantation the recipient developed a biliary stricture requiring surgery. One year after transplantation, her liver function was normal. Anthony K House, Gary P Jeffrey, Katherine A Edyvane, Andrew P Barker, Martin D Chapman, George Garas, John Ferguson,Peter V van Heerden, Neville M Gibbs, Dugal I Heath and Andrew W Mitchell MJA 2001; 175: 202-204 For editorial comment, see McCaughan and Lynch Clinical record - Recipient details - Donor details - Donor surgery - Recipient surgery - Postoperative details - Discussion - References - Authors' details - - More articles on Gastroenterology Without liver transplantation, the prognosis for fulminant hepatic failure is extremely poor.1 A shortage of cadaver donors has resulted in some patients dying while waiting for a suitable donor.2 In Western Australia, our experience is that 60% of patients with fulminant hepatic failure die before a cadaver liver becomes available. Living donor liver transplantation was initially developed to circumvent waiting list deaths in children. The technique was subsequently expanded to include adult patients because of insufficient availability of cadaveric organs.3 While adult-to-child living donor liver transplantation is a relatively safe and accepted practice,4 adult-to-adult living donor liver transplantation is still controversial. The concern is that, because adult recipients require larger grafts, healthy adult donors may be at greater risk of death or complications.5 The world experience in adult-to-adult living donor liver transplantation is rapidly increasing, and many studies show recipient outcomes similar to those with whole-organ implants, as well as low donor risk.2,3,6-9 To date, there have been no reports of adult-to-adult living donor liver transplantation in Australia. We report such a case. The Sir Charles Gairdner Hospital Human Ethics Committee approved an adult-to-adult living donor transplantation program. Clinical record Recipient details The recipient was a previously well, 71 kg, 19-year-old mother of a 15-month-old son. She had acquired hepatitis B virus (HBV) infection. Her admission on 15 April 2000 was preceded by 2-3 weeks of worsening jaundice and constitutional symptoms. Physical examination revealed deep jaundice, but no signs of chronic liver disease. At admission, the patient had a serum bilirubin level of 474 µmol/L (normal, < 20 µmol/L), serum alanine transferase (ALT) level > 300 U/L (normal, < 40 U/L), and an international normalised ratio of prothrombin time (INR) of 1.9. She tested positive for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), and negative for antibodies to hepatitis C and HIV. On the fifth day (20 April 2000), there was a marked clinical deterioration, with the development of unresponsive coma requiring intubation and ventilation. The patient met three King's College Hospital criteria for poor prognosis in fulminant hepatic failure: a time interval of more than seven days between jaundice and the onset of encephalopathy; a major disturbance in coagulation; and a serum bilirubin level > 300 mmol/L. The presence of these criteria suggested the likelihood of recovery without transplantation was less than 7%.10 On transfer to Sir Charles Gairdner Hospital, the patient fulfilled the Australasian and New Zealand liver group criteria for urgent listing for orthotopic cadaver liver transplantation. In the event of no cadaver liver becoming available, the possibility of a living donor liver transplant was discussed with the family. The recipient's mother, grandmother and two sisters volunteered as donors. On blood typing, her grandmother and a sister were found to be ABO blood group compatible. The sister was the more suitable donor as the grandmother had cardiovascular comorbidities. Donor details The donor was a 64 kg, 24-year-old woman, with no significant medical history. She smoked four cigarettes a day, but drank no alcohol. Preoperative evaluation by an independent psychiatrist demonstrated no psychosocial impediment to liver donation. Serum electrolyte levels, liver function tests, full blood analysis, and coagulation studies were normal, and serology for HIV and hepatitis B and C viruses was negative. An abdominal computed tomography scan showed a normal liver with a total volume of 1512 mL. The right lobe volume was estimated at 1133 mL, giving an estimated graft-to-recipient body weight ratio of > 1.0%; this was adequate for transplantation.11,12 Preoperative angiography showed the right hepatic artery arising from the superior mesenteric artery, and the left originating from the coeliac axis. Endoscopic retrograde cholangiopancreatography had to be abandoned because of patient intolerance. A magnetic resonance imaging cholangiogram showed conventional biliary anatomy, with the right anterior and posterior ducts joining 5 mm from the confluence of the right and left hepatic ducts. Five counselling sessions were conducted over two days between medical staff and the donor (with and without members of her family). Informed consent was obtained from the donor, with the understanding that the donor or her family could stop the process at any time without giving a reason. On the fifth day after referral to the transplant unit, the living donor liver transplantation from sister to sister proceeded concurrently in adjacent operating theatres. Donor surgery Donor surgery was performed as previously described through a right subcostal incision with a midline extension to the xiphoid process. 6,13 Before the completion of the donor right lobectomy, the recipient hepatectomy was commenced. Final clamping of the donor right lobe vessels was undertaken when the recipient was ready to receive the graft. The donor's total estimated blood loss for the procedure was 2000 mL, replaced by two units of packed red blood cells and one unit of autologous blood perioperatively. The total procedure time was 6 h 15 min. Recipient surgery The recipient surgery was through a similar incision. The entire liver, which was atrophic, heavily bile stained and showed massive hepatic necrosis histopathologically, was removed. The donor right lobe was implanted, hepatic vein end-to-side to the inferior vena cava ("piggyback" style). The other vessels and the right hepatic bile duct were joined end-to-end to the recipient structures. The total operative time was 10 h 10 min and the total ischaemic time was 55 min. The recipient required six units of packed red blood cells, 18 units of platelets and 24 units of fresh frozen plasma perioperatively. Immunosuppression was initiated with cyclosporin and methylprednisolone, together with prophylaxis for hepatitis B virus infection with hepatitis B immunoglobulin infusions and lamivudine. Postoperative details The donor was extubated several hours after leaving the operating theatre and, after 24 hours in the intensive care unit, was transferred to the general ward. Recovery was complicated by right basal atelectasis, which was treated by intensive chest physiotherapy. All liver function tests were normal at discharge on Day 6. A staphylococcal infection in the drain wound required a two-day readmission, but responded to flucloxacillin treatment. The donor returned to normal full activities four weeks later. The recipient made a slower postoperative recovery. There was an immediate improvement, and extubation occurred on the fifth day after surgery, with transfer to the general ward on Day 7. At this time her serum bilirubin level was 242 µmol/L, serum ALT level was 262 U/L, and INR was 1.2, improved from the pre-surgery values of 670 µmol/L, 1060 U/L and 5.1, respectively. Her serum lactate level was 8.1 mmol/L (normal, < 1.3 mmol/L). Complications included Staphylococcus aureus septicaemia, right middle and lower lobe consolidation, and an episode of severe acute graft rejection. On the 33rd day after surgery, the recipient was discharged. Two months after transplantation, her serum bilirubin level was 341 µmol/L, serum alkaline phosphatase level was 374 U/L (normal, 35-135 U/L), and serum ALT level was 80 U/L. A stricture of the biliary anastomosis was stented at this time. Three months after transplantation, there was still no filling of the right posterior bile duct, necessitating laparotomy and reanastomosis of the duct. The patient made an uncomplicated recovery and was discharged on Day 7. Persisting abnormal liver function tests at five and a half months led to a liver biopsy. Moderately severe chronic rejection was diagnosed, and the immunosuppressive medication was changed from cyclosporin to tacrolimus. At 12 months, results of liver function tests were normal and the recipient had returned to normal activities. Discussion This case represents the first adult-to-adult living donor liver transplantation in Australia. To date, there has been one reported adult-to-child living donor liver transplantation in Australia.14 The outcome of fulminant hepatic failure is extremely poor.10 Liver transplantation is the only effective treatment, but must be timely as delays result in sicker patients and higher mortality rates.15 In our patient, an urgent adult-to-adult living donor liver transplantation was undertaken because of the lack of availability of a cadaver graft. The reported experience of living donor liver transplantation in the high-urgency or emergency setting is limited, but internationally the outcomes are reported to be similar to conventional cadaver liver transplantation. Emergency living donor liver transplantation in 15 adults with fulminant hepatic failure had an overall patient survival rate of 59%,9 which is in the range reported for urgent cadaver transplantation (50%-68% survival at one year).1,16 In another series, adult patients with acute or chronic liver failure who were listed for high-urgency transplantation and received either living right lobe or extended living left lobe grafts had a one-year survival rate of 85%.2 As living donor liver transplantation exposes essentially healthy individuals to a life-threatening procedure, the processes of informed consent and patient selection must be strictly adhered to. Our donor volunteered early in the selection process. In accordance with the principle of self-selection or free voluntarism,2 care was taken to ensure there was no undue pressure on the potential donor from other family members. All members of the family understood they could stop the process at any time. If a potential donor does decide to withdraw from the process, this should remain confidential, and a medical excuse should be made for the cancellation.17 In our case, the donor made a speedy and uneventful recovery, but the recipient's recovery was complicated by a stricture at the biliary anastomosis. Biliary complications occur in 10%-35% of whole-organ cadaver transplants.17,18 Strictures are usually anastomotic and develop more than one month after surgery.19 Presently, there appears no clear benefit in using duct-to-duct biliary anastomoses or choledochojejunostomy.17,19 Three months after transplantation, our patient had a stricture corrected surgically. Recently, much attention has focused on a decline in the number of cadaveric organs available for emergency and elective transplantation. In Japan and Hong Kong, where there are critical shortages of cadaveric donors because of religious, cultural or legislative impediments, living donor liver transplantation has become an important adjunct to cadaveric transplantation.2,3 Some transplant centres in Japan and the United States have also been successfully using living donor liver transplants in the non-emergency setting.6 In Australia, between 6% and 8% of patients waiting for cadaver liver transplantation die each year, compared with 10% in the United States.20,21 Most of these patients are adults, as the number of children on the waiting list has been reduced significantly by the use of split liver cadaveric and living donor liver transplantation.22,23 Following the worldwide experience with living donor liver transplantation, the Transplant Society of Australia and New Zealand21 has recently supported the use of living donor liver transplantation in emergency situations, but has questioned its elective role because of concerns about donor safety and inadequate data demonstrating a local need. To date, there have been three reported deaths in 2000 living liver donors, giving a mortality rate of 0.15%.24,25 Case-series reports also indicate minimal donor morbidity, with minimal operative blood loss, and average lengths of stay of one week.2,7,8 Donor morbidities include minor and major complications in 30%. Of these, biliary strictures and cholestasis are the more prevalent.25 Adult living donor liver transplantation is likely to be extended to waiting list patients when death while waiting increases to the proportions reported from Europe and North America and after procedures are in place for recipient and potential donor to be fully informed at transplant listing. Donor mortality and morbidities are a serious issue, but can be minimised by adequate donor work-up and selection. References Bismuth H, Samuel D, Castaing D, et al. Orthotopic liver transplantation in fulminant and subfulminant hepatitis. Ann Surg 1995; 222: 109-119. Lo CM, Fan ST, Liu CL, et al. Applicability of living donor liver transplantation to high-urgency patients. Transplantation 1999; 67: 73-77. Inomata Y, Uemoto S, Asonuma K, et al. Right lobe graft in living donor liver transplantation. Transplantation 2000; 69: 258-264. Grewal HP, Thistlethwaite JR, Loss GE, et al. Complications in 100 living-liver donors. Ann Surg 1998; 228: 214-219. Strong RW. Whither living donor liver transplantation? Liver Transplant Surg 1999; 5: 536-538. Marcos A, Fisher RA, Ham JM, et al. Right lobe living donor liver transplantation. Transplantation 1999; 68: 798-803. Fan ST, Lo CM, Liu CL, et al. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000; 135: 336-340. Marcos A, Fisher RA, Ham JM, et al. Selection and outcome of living donors for adult to adult right lobe transplantation. Transplantation 2000 (a); 69: 2410-2415. Uemoto S, Inomata Y, Sakuri T, et al. Living donor liver transplantation for fulminant hepatic failure. Transplantation 2000; 70: 152-157. O'Grady JG, Alexander GJM, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1997; 97: 439-445. Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 1999; 67: 321-327. Marcos A, Fisher RA, Ham JM, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation 2000 (b); 69: 1375-1379. Wachs ME, Bak TE, Karrer FM, et al. Adult living donor liver transplantation using a right hepatic lobe. Transplantation 1998; 66: 1313-1316. Strong RW, Lynch SV, Ong TN, et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 322: 1505-1507. Shakil AO, Mazariegos GV, Kramer DJ. Fulminant hepatic failure. Surg Clin North America 1999; 79: 77-108. Washburn WK, Bradley J, Cosimi AB, et al. A regional experience with emergency liver transplantation. Transplantation 2000; 61: 235-239. Marcos A. Right lobe living donor liver transplantation: A review. Liver transplantation 2000; 6: 3-20. Jeffrey GP, Brind AM, Ormonde DG, et al. Management of biliary tract complications following liver transplantation. Aust N Z J Surg 1999; 69: 717-722. Mazariegos GV, Molmenti EP, Kramer DJ. Early complications after orthotopic liver transplantation. Surg Clin North America 1999; 79: 109-129. Kam I. Anatomical variations of the liver. Technical issues with Donors and Outcomes. The Second International Symposium Dedicated to Expanding the Donor Pool, Living Donor and Split Liver Transplantation; XVIII International Congress of the Transplantation Society 2000. Transplant Society of Australia and New Zealand (TSANZ). Live donor liver transplantation in Australia: Current recommendations. Liver Transplant Standing Committee. April 2000: Canberra, Australia. Rogier X, Broering DC, Mueller L, Living-donor liver transplantation in children. Langenbecks Arch Surg 1999; 384(6): 528-535. Reding R, de Goyet J de V, Delbeke I, et al. Paediatric liver transplantation with cadaveric or living related donors. Comparative results in 90 elective recipients of primary grafts. J Paediatr 1999; 134(3): 280-286. Schiano TD, Kim-Schluger L, Gondolesi G, Miller CM. Adult living donor transplantation. The hepatologist's perspective. Hepatology 2001; 33: 3-8. Renz JF, Roberts JP. Long-term complications of living donor liver transplantation. Liver Transpl 2000; 6 Suppl 2: 73-76. (Received 18 Apr 2001, accepted 22 Jun 2001) Authors' details Liver Transplant Service of Western Australia, Sir Charles Gairdner Hospital, Perth, WA. Anthony K House, MS, FRACS, Professor, Department of Surgery, University of Western Australia; Gary P Jeffrey, MD, FRACP, Associate Professor, Department of Medicine, University of Western Australia; Katherine A Edyvane, BM, BS, Registrar; Andrew P Barker, MB BS, FRACS, Surgeon; Martin D Chapman, MB BS, FRANZCP, Psychiatrist; George Garas, MB BS, FRACP, Hepatologist; John Ferguson, MB ChB, MRCP, Radiologist; Peter V van Heerden, Mmed, PhD, Intensivist; Neville M Gibbs, MD, FANZCA, Anaesthetist; Dugal I Heath, MD, FRACS, Surgeon and Senior Lecturer, Department of Surgery, University of Western Australia; Andrew W Mitchell, MB BS, FRACS, Senior Lecturer, Department of Surgery, University of Western Australia. Reprints will not be available from the authors. Correspondence: Professor A K House, University Department of Surgery, QEII Medical Centre, M Block, Verdun Road, Nedlands, WA 6907. akhouseATcyllene.uwa.edu.au Make a comment

Anthony K House · Gary P Jeffrey · Katherine A Edyvane · Andrew P Barker · Martin D Chapman · George Garas · John Ferguson · Neville M Gibbs

In 1993, a group of researchers led by Andrew Wakefield at the Royal Free Hospital, London, suggested an association between both wild and vaccine measles viruses and inflammatory bowel disease (IBD), based on a small case series of children with Crohn's disease.1 In 1998, the same researchers reported another series of 12 children, and described an apparently new syndrome of an unusual type of IBD associated with developmental disorders such as (but not limited to) autism.2 They suggested that measles-mumps-rubella (MMR) vaccine may cause IBD, resulting in decreased intestinal absorption of essential vitamins and nutrients and possibly leading to developmental disorders such as autism. Wakefield has also expressed the opinion (without any scientific evidence) that such perturbations are less likely if the components of MMR are given separately, spaced several months apart. Measles remains one of the most severe infectious childhood diseases (Box), and the current vaccine is 95% effective. Yet parents worry about sensational media reports of possible links between vaccines and a variety of medical conditions. Autism and IBD (Box) and their alleged relationship to MMR vaccine have recently been highlighted in the media. Epidemiological evidence Expert groups around the world have expressed the opinion that the suggested associations between the MMR vaccine, IBD and autism are weak and the studies flawed. The studies at the Royal Free Hospital1,2 were conducted on highly selected patients referred for gastrointestinal ailments. The studies had no controls, were unblinded and were not designed to test aetiology or harm. There were multiple potential sources of bias. For example, the association between vaccination and autism was based primarily on parental recall — parents are likely to link changes in behaviour with memorable events such as vaccination, thereby introducing "recall" bias. Such a case-series analysis is unable to determine causal links. Moreover, the onset of autism and MMR vaccination may appear to be associated in time because the average age at which parents report concerns about child development is 18-19 months and most children receive MMR vaccine before their second birthday. In contrast to Wakefield and colleagues' two small, poorly designed studies,1,2 large, well designed epidemiological studies have shown no association between MMR vaccine and autism. These include a UK population-based study of the vaccination status of 498 children with autism,6 a study of the rates of IBD and autism among 6100 French schoolchildren,7 and an examination of trends in the incidence of autism and MMR vaccine coverage over time in California3 and in UK general practices.4 Similarly, a Finnish study of 1.8 million children over 14 years that looked at adverse events after MMR vaccination did not document a single case of autism or IBD as a consequence of MMR vaccination.8 Virological evidence In their 1993 study, Wakefield and colleagues reported identification of measles virus in bowel tissue of patients with Crohn's disease.1 Other laboratory studies using similar methodology have not found measles virus in patients with IBD. In fact, one group suggested that the reported "measles virus" represented a cross-reaction with another protein structurally similar to certain measles antigens.9 More sensitive testing methods have not revealed any evidence of measles virus in the gut of patients with Crohn's disease or ulcerative colitis.10Recently, Wakefield and O'Leary presented data to the Immunisation Safety Committee of the US Institute of Medicine suggesting that measles virus has been detected by very sensitive polymerase chain reaction (PCR) methods in the gut of selected autistic children.11 These data have not been published in the peer-reviewed scientific literature. Kawashima and colleagues in Japan have published a study reporting the detection of measles virus by PCR in peripheral mononuclear cells of individuals with autism and bowel disease. However, these findings have not been replicated by other laboratories, and most studies have found no evidence for the presence of measles virus in the gut in inflammatory disease.11 Interestingly, there was no mention of detection of vaccine viruses in the bowel or brain tissues of any patients in the 1998 study of Wakefield and colleagues,2 in contrast with their 1993 report.1 Level of evidence Wakefield's studies provide very weak (National Health and Medical Research Council Level IV) evidence for harm or causation relating to the MMR vaccine.12 The "Bradford Hill" criteria for causation13 are poorly fulfilled by Wakefield's studies.1,2 Specifically, there is no estimate of the strength of association, no evidence of a dose-response relationship or temporal sequence, no consistent findings from other investigators, no coherence with established facts, and poor specificity of association.14In addition to there being no evidence to support a causal relationship between MMR and autism, Wakefield's proposal that the vaccine components of MMR be given separately is unsupported by any evidence. Indeed, giving these vaccines separately has many disadvantages. First, children will receive some components later than recommended, risking exposure and infection in the intervening time. Second, there are additional injections and some may be omitted, or viral interference may reduce vaccine effectiveness if components are given separately but too close together. Except for monovalent rubella, these vaccines are not currently available separately in Australia, and requests to give them separately should be strenuously resisted. Consensus about the safety of MMR by expert groups The World Health Organization rejects an association between MMR and autism, and "strongly endorses the use of MMR . . . vaccine on the grounds of its convincing record of safety and efficacy".15 In 1998, a meeting of the British Medical Research Council and a group of national and international experts concluded that there was "no evidence to indicate any link between MMR vaccination and bowel disease or autism".16 In April 2001, the Institute of Medicine released its report Immunization safety review: measles-mumps-rubella vaccine and autism,11which concluded that the available evidence rejects a causal association between MMR and autism, although recommending that further research into the issue be conducted because of public concern. In view of considerable epidemiological evidence on the safety of MMR vaccine, we believe that Wakefield's small, unsubstantiated case series should be seen in correct perspective, and that parents and healthcare professionals should be reassured that there is no evidence that the MMR vaccine is associated with autism or IBD. C Raina MacIntyre Senior Lecturer Peter B McIntyre Deputy Director National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, Children's Hospital, Westmead, NSW. rainamAToptusnet.com.au Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn's disease. J Med Virol 1993; 39: 345-353. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998; 351: 637-641. Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 2001; 285: 1183-1185. Kaye JA, del Mar Melero-Montes M, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001; 322: 460-463. Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29: 769-786. Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026-2029. Fombonne E, Du Mazaubrun C, Cans C, Grandjean H. Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997; 36: 1561-1569. Patja A, Davidkin I, Kurki T, et al. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatr Infect Dis J 2000; 19: 1127-1134. Iizuka M, Chiba M, Yukawa M, et al. Immunohistochemical analysis of the distribution of measles related antigen in the intestinal mucosa in inflammatory bowel disease. Gut 2000; 46: 163-169. Afzal MA, Armitage E, Ghosh S, et al. Further evidence of the absence of measles virus genome sequence in full thickness intestinal specimens from patients with Crohn's disease. J Med Virol 2000; 62: 377-382. Institute of Medicine. Immunization safety review: measles-mumps-rubella vaccine and autism. Washington, DC: National Academy Press, 2001. Available at: <http://books.nap.edu/html/mmr> (Accessed 4 July 2001). Levine M, Walter S, Lee H, et al. Users' guides to the medical literature. IV. How to use an article about harm. Evidence-Based Medicine Working Group. JAMA 1994; 271: 1615-1619. Wilkinson L. Sir Austin Bradford Hill: medical statistics and the quantitative approach to prevention of disease. Addiction 1997; 92: 657-666. Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000. Pediatrics 2001; 107(5): 1-23. World Health Organization. Statement on the use of MMR vaccine. Available at: <http://www.who.int/vaccines-diseases/safety/hottop/mmrstatement.htm> Accessed 4 July 2001. Medical Research Council. Report from the Working Party on MMR. London: MRC, 1998. Make a comment Measles, inflammatory bowel disease and autism Measles Measles is virtually universal among unimmunised children in all countries: 99.9% of unimmunised people will contract measles, 90% before the age of 20. One in every 5000-10000 cases results in death from the acute effects of the disease. Worldwide, there were 888000 deaths due to measles in 1998, more than the number due to breast or skin cancer, homicide or violence. Inflammatory bowel disease (IBD) IBD is a group of chronic inflammatory disorders of the small and large bowel, the commonest being ulcerative colitis and Crohn's disease. The cause of IBD is not understood, but both an immune mechanism and a genetic predisposition are probably involved. IBD is relatively rare, with an incidence of 6-8 cases per 100000 population for ulcerative colitis and 2 cases per 100000 for Crohn's disease. It usually occurs in people aged between 15 and 30 years, but can occur in children. Autism Autism is a developmental disorder that is usually identified between the ages of 18 months and three years. Four times more common in boys than girls, autism occurs in all racial and social groups. Autistic children and adults typically have difficulties in verbal and non-verbal communication, social interactions and leisure or play activities. A single cause of autism has not been identified, but current research implicates neurodevelopmental, genetic and environmental factors. The sex differential suggests a strong genetic component. Many children have some features of autism but do not fulfil all the diagnostic criteria. There has been an apparent increase in the incidence of autism in recent decades. In the United States the rate increased from 44/100000 births in 1980 to 208/100000 births in 1994,3 while in the United Kingdom the rate increased from 3/100000 births in 1988 to 21/100000 births in 1999.4 This has been attributed largely to changing case definitions and classifications (which now include less severe forms of the disease) and improved recognition.5 The discrepancy between the US and UK rates may be evidence of inconsistent case definitions. It is uncertain how much, if any, of the increased incidence is independent of diagnostic practice. Back to text

Editorials Awareness during general anaesthesia: is it worth worrying about? Bispectral index monitoring may be a solution to the problem MJA 2001; 174: 212-213 Patients rightfully expect that they will have no memory of their surgery when it is performed under general anaesthesia. However, the incidence of postoperative recall of intraoperative events ("awareness") is about 1 in 1000 in patients undergoing non-cardiac surgery and greater than 3 in 1000 in cardiac surgical patients.1 As about two million general anaesthetics are performed each year in Australia, about 2000 patients will suffer an episode of awareness. This makes awareness one of the most common serious complications of anaesthesia.1-7Chilling accounts of intraoperative awareness abound in the medical literature and lay press.3,8,9 Patients who have experienced awareness during anaesthesia report the perception of paralysis, conversations, and surgical manipulations, accompanied by feelings of helplessness, fear and pain. While patients usually recognise the event as real, few are willing to report the experience to their anaesthetist for fear of being disbelieved or ridiculed. Post-traumatic stress disorder may develop as a devastating sequel of awareness.9 Why does awareness occur? Anaesthetic requirement is a balance between the amount of anaesthetic administered and the state of arousal of the patient. During any operation, the intensity of stimulation varies markedly, with the most potent noxious stimulus, endotracheal intubation, occurring at the beginning of the procedure. At the same time, the haemodynamic effects of the anaesthetic drugs may limit the amount that can be safely given. Thus, critical imbalances between anaesthetic requirement and delivery may occur. Marked interindividual variation in anaesthetic requirement, the use of muscle relaxants, and lack of a proven monitor for awareness compound the problem. In addition, awareness may occur as a result of anaesthetist error or technical mishaps.10 In an era of sophisticated intraoperative monitoring, it may surprise many non-anaesthetists (and our patients) that we are unable to guarantee loss of consciousness during surgery. A definitive monitor for awareness has been described as the "Holy Grail" of anaesthesia.11 Clinical signs of somatic or autonomic responsiveness have always been the mainstay of anaesthetic depth monitoring, but they lack proven utility in detecting awareness.5 Other techniques (the isolated forearm technique,12 frontalis electromyogram13 and lower-oesophageal contractility14) have similarly been unreliable. Promising technologies such as auditory evoked potential15 and heart-rate variability16 monitoring await wide availability and acceptance into clinical practice. Many attempts have been made to produce a simplified interpretation of the electroencephalograph (EEG) that predicts anaesthetic depth,11 but, in most cases, these were unsatisfactory.17 Recently, sophisticated pattern recognition systems that assess multiple features of the EEG have been developed. One such monitor, the bispectral index (BIS) (Aspect Medical Systems Inc, MA, USA), displays a single number derived from bispectral analysis of the EEG. The BIS ranges from 0 to 100, values below 60 being associated with unconsciousness. It has been shown to be a reliable indicator of level of consciousness18,19 and to improve operating room utilisation and reduce costs (by allowing faster patient turnover and reducing the use of drugs).18 Is BIS monitoring a reliable method of detecting and preventing awareness during anaesthesia? According to Aspect Medical Systems' product information, more than 1.2 million patients have been monitored with BIS and only 41 have reported awareness. Many of those experiencing awareness recorded a BIS value of greater than 65. This low reporting rate either represents an underestimate of the true incidence of awareness or reflects the effectiveness of BIS monitoring in preventing awareness. A suitably designed randomised trial could help to answer this clinically important question,20 although it has been argued that the low incidence of awareness under anaesthesia would necessitate a prohibitively large trial (about 50 000 patients).7,21 However, if a high-risk group could be identified, adequate power could be achieved with a much smaller sample size.20 Obstetric, cardiac and trauma patients are among those who are more likely to report awareness during anaesthesia.2 A study of 2300 patients in this group would be sufficient to reliably detect a decrease in incidence of awareness from 1% to 0.1% resulting from a more effective monitor (a = 0.05; b = 0.2). This large treatment effect is realistic for two reasons: (i) the acceptance of a monitor into routine anaesthetic practice would require a convincing demonstration of benefit; and (ii) the rate of awareness during BIS monitoring is thought to be extremely low. We are currently undertaking such a trial in Australia, New Zealand and Hong Kong (for further details, see our website at <http://www.b-aware-trial.org>). While widespread use of BIS would certainly incur considerable cost for acquisition and ongoing expenses, this should be balanced against the ability of BIS monitoring to improve anaesthetic drug titration (thereby decreasing drug and recovery-room costs18), the potential to prevent costly litigation, and the possibility of reducing the level of patient anxiety about awareness (up to 54% of patients due to undergo surgery are concerned about awareness6). We believe that if a monitor was proven to decrease the incidence of awareness in an appropriately designed and conducted trial, the costs would be justified. Our patients expect nothing less. Kate Leslie Anaesthetist, Royal Melbourne Hospital, Melbourne, VIC Honorary Senior Fellow, Department of Pharmacology, University of Melbourne kate.leslieATmh.org.au Paul S Myles Head of Anaesthesia Research Alfred Hospital, Melbourne, VIC Associate Professor Department of Epidemiology and Preventative Medicine, Monash University Competing interests: Aspect Medical Systems Inc have provided some funding for a multicentre awareness monitoring trial (the B-Aware Trial), designed and independently conducted by us. Dowd M, Cheng D, Karski J, et al. Intraoperative awareness in fast-track cardiac anaesthesia. Anesthesiology 1998; 89: 1068-1073. Liu W, Thorp T, Graham S, et al. Incidence of awareness with recall during general anaesthesia. Anaesthesia 1991; 46: 435-437. Lyons G, Macdonald R. Awareness during Caesarean section. Anaesthesia 1991; 46: 62-64. Ranta S, Ranta V, Aromaa U. The claims for compensation for awareness with recall during general anaesthesia in Finland. Acta Anaesthesiol Scand 1997; 41: 356-359. Phillips A, McLean R, Devitt J, et al. Recall of intraoperative events after general anaesthesia and cardiopulmonary bypass. Can J Anaesth 1993; 40: 922-926. Myles P, Williams D, Hendrata M, et al. Patient satisfaction after anaesthesia and surgery: results of a prospective survey of 10,811 patients. Br J Anaesth 2000; 84: 6-10. Sandin R, Enlund G, Samuelsson P, et al. Awareness during anaesthesia: a prospective case study. Lancet 2000; 355: 707-711. Macleod AD, Maycock E. Awareness during anaesthesia and post traumatic stress disorder. Anaesth Intensive Care 1992; 20: 378-382. Cobcroft M, Forsdick C. Awareness under anaesthesia: the patients' point of view. Anaesth Intensive Care 1993; 21: 837-843. Domino K, Posner K, Caplan R, et al. Awareness during anesthesia: a closed claims analysis. Anesthesiology 1999; 90: 1053-1061. Todd M. EEGs, EEG processing, and the bispectral index. Anesthesiology 1998; 89: 815-817. Bogod D, Orton J, Oh T. Detecting awareness during general anaesthetic caesarian section. Anaesthesia 1990; 45: 279-284. Edmonds HL. Anesthetic adequacy, surface EMG, and quantitated EEG. Acta Anaesthesiol Scand 1993; 37(Suppl 100): 102-104. Raftery S, Enever G, Prys RC. Oesophageal contractility during total i.v. anaesthesia with and without glycopyrronium. Br J Anaesth 1991; 66: 566-571. Thornton C, Konieczko K, Jones JG, et al. Effect of surgical stimulation on the auditory evoked response. Br J Anaesth 1988; 60: 372-378. Sleigh J, Donovan J. Comparison of bispectral index, 95% spectral edge frequency and approximate entropy of the EEG, with changes in heart rate variability during induction of general anaesthesia. Br J Anaesth 1999; 82: 666-671. Sigl JC, Chamoun NG. An introduction to bispectral analysis for the electroencephalogram. J Clin Monit 1994; 10: 392-404. Gan T, Glass P, Windsor A, et al. Bispectral Index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. Anesthesiology 1997; 87: 808-815. Leslie K, Sessler DI, Schroeder M, et al. Propofol blood concentration and the Bispectral Index predict suppression of learning during propofol/epidural anesthesia in volunteers. Anesth Analg 1995; 81: 1269-1274. Myles P. Why we need large randomized studies in anaesthesia. Br J Anaesth 1999; 83: 833-834. Simini B. Awareness of awareness during general anaesthesia. Lancet 2000; 355: 672-674.

Kate Leslie · Paul S Myles

Position Statement Non-valvular atrial fibrillation and stroke prevention Graeme J Hankey, on behalf of the National Blood Pressure Advisory Committee of the National Heart Foundation* MJA 2001; 174: 234-239 Abstract - Warfarin versus control - Aspirin versus control - Warfarin versus aspirin - Warfarin combined with aspirin - Warfarin versus other antiplatelet agents - Who to treat and with what? - Who is at high risk of stroke and thromboembolism without treatment? - Who is at high risk of haemorrhage with anticoagulant treatment? - Recommendations for antithrombotic therapy for AF - References - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Atrial fibrillation (AF) affects 5% of people older than 65 years. Among patients with AF, the risk of stroke averages about 5% per year. The risk of stroke increases cumulatively with increasing age, previous transient ischaemic attack or stroke, hypertension, diabetes, impaired left ventricular function and a large left atrium. Management aims to identify and treat the underlying cause, control the ventricular rate, restore and maintain sinus rhythm, and minimise the risk of stroke. Warfarin reduces the risk of stroke by about two-thirds, and aspirin by about one-fifth. The risk of anticoagulant-associated haemorrhage increases with serious concomitant disease, and with poorly controlled hypertension and poorly controlled anticoagulation. All patients with chronic AF should be considered for oral anticoagulant therapy, and the decision based on the balance between the risks of thromboembolism and bleeding. The recommended INR (international normalised ratio) is 2.0-3.0. Treating 1000 "average" AF patients (ie, those with a 5% per year risk of stroke) with warfarin prevents about 30 strokes and causes at least two episodes of major haemorrhage each year. Treating 1000 AF patients with aspirin prevents about 15 strokes each year. Atrial fibrillation (AF) is a common arrhythmia. Its prevalence increases with age, from about 2% in the general population, to 5% in people older than 65 years, and 10% in people older than 75 years1,2 (E4; level-of-evidence codes are described in Box 13). It may occur as a single episode, a series of recurrent episodes ("paroxysmal" AF), or continuously ("permanent" or "chronic" AF). Atrial fibrillation is an important arrhythmia because it may signify underlying heart disease, it may cause symptoms of decreased cardiac output (eg, malaise, effort intolerance) or palpitations, and it is associated with an increased risk of systemic thromboembolism and stroke. This risk of stroke averages about 5% per year among all individuals in AF, which is about 5-6 times greater than for people of the same age who are in sinus rhythm (E32).1,2 The management of AF has four principal objectives: To confirm and document the arrhythmia; To identify and treat the underlying cause; To relieve symptoms of decreased cardiac output by controlling the ventricular rate and restoring and maintaining sinus rhythm; and To reduce the risk of systemic thromboembolism, particularly stroke. All patients, except perhaps the very elderly and infirm, should undergo investigation for underlying causes of AF, including thyroid function tests and echocardiography (E4).4 In haemodynamically stable patients, β-blockade, verapamil or diltiazem can be used to control the heart rate (E4). Recent-onset AF reverts spontaneously within 24 hours in at least half of patients (irrespective of whether or not they are taking digoxin) (E33).5 Patients who have been in AF for more than 48 hours should be considered for anticoagulation therapy and strategies to restore and maintain sinus rhythm. Warfarin should be administered for three weeks before cardioversion is attempted.6 If cardioversion can not be postponed for three weeks, the patient should undergo anticoagulation therapy with intravenous heparin and warfarin,7 and be considered for transoesophageal echocardiography (TOE) (E32). Cardioversion can probably be undertaken safely (with limited risk of stroke) if TOE excludes left atrial and appendage thrombus (and the patient is treated with heparin and warfarin) (E2).8,9 However, if transoesophageal echocardiography identifies left atrial and appendage thrombus, then cardioversion is contraindicated until the patient has been anticoagulated for at least three weeks (E4). The relative merits of cardioversion by electrical shock and medical therapy have been discussed recently.4,10 Direct current cardioversion has never been subjected to a randomised trial, but appears to be the most effective method of restoring sinus rhythm. Its main disadvantage is the need for general anaesthesia. Digoxin and verapamil are ineffective for converting AF to sinus rhythm. Flecainide or sotalol are the preferred medical therapies in younger patients without structural heart disease, and amiodarone in older patients (E2).11 The chances of successful cardioversion are greater if the AF is of recent onset and the left atrial size is normal (E33).12 After successful cardioversion, warfarin therapy should be continued for at least four weeks to prevent clot formation in the "stunned" left atrium (E33).13,14 Antiarrhythmic drug therapy should also be continued to prevent recurrent AF, but this still occurs in 40%-50% of patients after 12 months' follow-up despite drug therapy. If the patient has a low risk of recurrence of AF (eg, "lone" AF) and remains in sinus rhythm for one month after cardioversion, anticoagulation therapy with warfarin can be ceased (E4). In patients at higher risk of recurrence (Box 2), it may be more appropriate to continue warfarin therapy for longer or indefinitely (E4). For patients who are elderly (in whom AF is usually chronic and antiarrhythmic drug therapy may be risky) or have asymptomatic chronic AF, it is often reasonable to avoid attempted cardioversion, accept the AF and aim for adequate ventricular rate control (digoxin combined with β-blockade, verapamil or diltiazem) and long term anticoagulation therapy (E4). The results of clinical trials in patients with asymptomatic AF (of rate control and antithrombotic therapy versus attempted cardioversion and maintenance of sinus rhythm to avoid warfarin) are awaited. Strategies for reducing the risk of stroke and systemic thromboembolism in patients with AF have been studied in several randomised controlled trials over the past decade.15-25 Warfarin versus control Primary prevention Five large randomised controlled primary prevention trials have shown that, in people with chronic non-valvular AF, warfarin reduced the risk of stroke by about two-thirds (68%; 95% CI, 50%-79%; P < 0.001), from about 4.5% to 1.4% per year overall, with little increase in frequency of major bleeding (warfarin, 1.2%; control, 1.0%), or intracranial haemorrhage (warfarin, 0.3% per year; control, 0.1% per year) (E1).15-19,26 This means that warfarin will prevent about 30 strokes per 1000 patient-years of treatment at a cost of at least two serious bleeding episodes per 1000 patients treated for one year. It must be stressed, however, that this acceptable rate of bleeding was achieved in patients who were carefully selected, screened and closely followed; 53%-93% of eligible patients with AF were not included in the trials because of an increased risk of bleeding. Exclusion criteria included old age (> 75 years), serious illness (liver, kidney, brain or malignant disease), alcoholism, fall risk (eg, syncope), forgetfulness, non-steroidal anti-inflammatory drug therapy, and uncontrolled hypertension. Secondary prevention One secondary prevention trial (the European Atrial Fibrillation Trial [EAFT]) showed that, in people with chronic non-valvular AF and symptoms of previous transient ischaemic attack (TIA) or stroke, who have a risk of stroke of 12% per year, warfarin therapy (target INR, 2.5-4.0) reduced the risk of stroke by about two-thirds (66%; 95% CI, 53%-80%), to 4% per year (E2).20 The annual incidence of major bleeding complications was 2.8% in the anticoagulant group and 0.7% in the placebo group. No intracranial bleeds were identified in patients assigned to warfarin. Thus, warfarin prevents about 80 strokes per 1000 patient-years in patients who have had a TIA or stroke and who are in AF, at a cost of at least 20 serious bleeding episodes per 1000 patients treated for one year. The timing of anticoagulation therapy after recent ischaemic stroke depends on the risk of recurrent thromboembolism (Box 2) and the risk of haemorrhagic transformation of the brain infarct (which is higher within the first two weeks and in patients with large brain infarcts and uncontrolled hypertension [E32]27). Common empirical practice is to treat patients with fibrillating acute ischaemic stroke immediately with aspirin (300 mg daily) and then, depending on the above factors, begin warfarin (5 mg daily) between days three and 14 after stroke onset, aiming to achieve an INR of 2.0.28 However, randomised trials comparing aspirin with heparin during the first two weeks of acute ischaemic stroke among patients in AF show no benefit from early anticoagulation, because any net gains from reduction in recurrent ischaemic stroke are offset by the excess hazards of haemorrhagic stroke (E1).29,30 Aspirin versus control Three primary prevention and three secondary prevention trials have shown that, in people with AF, aspirin reduced the incidence of stroke by 22% (95% CI, 2%-38%), from 5.2% (placebo) to 3.7% (aspirin) per year for primary prevention (absolute risk reduction: 1.5% per year), and from 12.9% (placebo) to 10.4% (aspirin) per year for secondary prevention (absolute risk reduction, 2.5% per year) (E1).31Aspirin was not associated with any significant excess of intracranial haemorrhage (aspirin, 0.16%; control, 0.13%) or major extracranial bleeding (aspirin, 0.5%; control, 0.6%) (E1).31 This means that aspirin might prevent about 10 to 20 strokes per 1000 patient-years of treatment, depending on the type of patient treated and their baseline risk of stroke, with little risk of major bleeding. A speculative interpretation of these data is that, in patients with AF, aspirin prevents strokes due to atherothromboembolism, but not cardiogenic embolism. This interpretation is based on the magnitude of the effect (a 20% relative risk reduction), which is very similar to the effect of aspirin in patients with symptomatic atherothromboembolism of the brain, heart and limbs.32 Whether aspirin combined with adjusted-dose warfarin would be safe and more effective (in preventing both atherothrombotic and cardiogenic strokes) than warfarin alone in patients with AF remains unknown.33 Warfarin versus aspirin The relative benefits and risks of warfarin and aspirin have been studied in three trials,15,20,21 all of which showed that warfarin was associated with half the risk of stroke compared with aspirin (47% relative risk reduction; 95% CI, 28%-61%; P < 0.01) (E1).26 Warfarin combined with aspirin For patients with AF who are at high risk of stroke, adding aspirin (325 mg daily) to low-intensity, fixed-dose warfarin, adjusted to an INR of 1.2-1.5, was not as effective in preventing stroke or systemic thromboembolism as standard adjusted-dose warfarin therapy, maintaining an INR of 2.0-3.0 (event rates, 7.9% per year v. 1.9% per year, respectively; P < 0.0001), and there is no difference in the rates of major bleeding (E2).22 Three subsequent trials also suggested that adjusted-dose warfarin (INR, 2.0-3.0) was superior to low-intensity anticoagulant therapy or an aspirin- anticoagulation regimen (E1).23-25 Warfarin versus other antiplatelet agents An Italian study reported that a new antiplatelet agent, indobufen (100-200 mg twice daily), was as effective as adjusted-dose warfarin (INR, 2.0-3.5) in preventing stroke, systemic embolism, myocardial infarction or vascular death in 916 patients with non-valvular AF and recent (within 15 days) TIA or non-disabling ischaemic stroke (E2).34 The 12-month event rates were 10% in the warfarin group and 12% in the indobufen group (P = 0.47). However, the number of patients and outcome events were quite small, follow-up was short, and it is possible that a true difference was not detected. Future studies are planned to evaluate the safety and effectiveness of other, newer antiplatelet agents (such as clopidogrel, oral glycoprotein IIb/IIIa receptor inhibitors, and oral thrombin inhibitors) and combination antiplatelet therapies (such as aspirin-ticlopidine, aspirin-clopidogrel, and aspirin-dipyridamole) as strategies of thromboprophylaxis in AF. Who to treat and with what? Not all patients with AF benefit from thromboprophylactic treatment. The decision to treat depends on the balance between the risk of thromboemboli without treatment and the risks of thromboemboli and haemorrhage with treatment in each patient, as well as the patient's willingness to accept the potential risks, costs, and inconvenience of treatment in order to possibly benefit. The current profile of individual risk of thromboembolism and bleeding complications (see below) remains imprecise and continues to be refined as new data emerge.7 Who is at high risk of stroke and thromboembolism without treatment? The important independent prognostic factors for an increased risk of stroke among individuals with AF are increasing age, a history of previous TIA or stroke, hypertension, diabetes mellitus, and transthoracic echocardiographic evidence of moderate to severe left ventricular systolic dysfunction (E1).7,26,35-37 Echocardiographic evidence of left atrial enlargement (E2) and left atrial spontaneous echo densities ("smoke"), possibly indicative of stasis of blood, are also significant risk factors for stroke36-39 (E33). These risk factors are cumulative: for people younger than 65 years with no risk factors the untreated annual risk of stroke is about 1%, whereas with one or more risk factors it is about 5%; for people aged 65-75 years with no risk factors the annual risk of stroke is about 4%, and with one or more risk factors it is about 6% per year; and for people older than 75 years with no risk factors the risk of stroke is about 3%-4%, whereas with one or more risk factors it is about 8% (see Box 2) (E1).7,26 Who is at high risk of haemorrhage with anticoagulant treatment? The major risk factors for anticoagulant-associated intracranial haemorrhage include fragile intracranial blood vessels (previous symptomatic cerebrovascular disease, computed tomography brain scan evidence of small vessel disease ["leukoaraioisis"]), high blood pressure (poorly controlled hypertension), and excessive anticoagulation (INR, > 3.5) or factors predisposing to it, such as confusion, dementia, inadequate anticoagulant monitoring, alcoholic liver disease, and a tendency to falls (E2).40,41 Increasing age is a risk factor for all of these risk factors, and is thus a potent risk factor for anticoagulant-associated haemorrhage. Among a subgroup of patients in the Stroke Prevention in Atrial Fibrillation (SPAF) II trial (mean age, 80 years), the rate of intracranial haemorrhage was as high as 1.8% per year in those allocated to warfarin therapy (target INR, 2.0-4.5) and 0.8% among those who were assigned to aspirin (E2).21 Although the target INR in this study was higher than currently recommended (INR, 2.0-3.0), these data suggest that the low rate of intracranial haemorrhage documented in the five primary prevention AF trials15-19 may not apply to very elderly individuals (who were not well represented in many of these trials -- the mean age of the patients studied in the AF trials was 69 years, and only about a quarter were older than 75 years). Recommendations for antithrombotic therapy for AF Current practice necessitates individualisation of therapy after an integrated clinical assessment that evaluates thromboembolic risk due to AF, other potential indications for anticoagulant therapy, risk of haemorrhage, and non-medical factors relating to compliance, capacity to have the INR monitored at least monthly, gait instability, risk of other trauma, and patient values and preferences.42,43 Decision analysis can also be useful.44The role of transthoracic echocardiography (TTE), in addition to excluding structural heart disease in all patients who first present with AF, is to further refine stroke risk in the small group of patients with a low risk of stroke according to clinical factors. Although TOE is more sensitive in detecting left atrial thrombus and spontaneous echo contrast, which are markers for increased risk of thromboembolism,36-39 it is more invasive and is usually only required to improve risk stratification among individuals with a relative contraindication to warfarin or in whom TTE is inadequate. The choices of thromboprophylactic agents for atrial fibrillation include warfarin, which is the most effective but also the most risky treatment, and aspirin, which is less effective than warfarin but safer (E1). The combination of aspirin and low dose warfarin is no more effective than aspirin alone (E1).22,23 The most appropriate treatment regimen is one in which patients at high risk of stroke and low risk of haemorrhage are treated with warfarin, and patients at low risk of stroke or high risk of haemorrhage are treated with aspirin. Who not to treat Individuals with AF who are aged less than 60 years and have no evidence of any concurrent heart disease have a very low risk of a thromboembolic event (about 0.6% per year).45 The potential benefits of aspirin in these patients (which may reduce the risk of stroke by 0.12% per year [20% of 0.6%]) may be offset by an equal potential risk of aspirin-associated haemorrhagic stroke of 0.12%.46 Who to treat with aspirin Aspirin is indicated for individuals in AF who are at fairly low absolute risk of stroke, such as those without any of the independent thromboembolic risk factors listed above, or those at risk of an anticoagulant-related haemorrhage which exceeds the risk of stroke (more than 1% per year) (E1). For some people, such as the elderly and those with hypertension, whose risks of stroke and haemorrhage are both high, the treatment decision can be difficult, and may be determined ultimately by the patient's preferences.42,43Patients taking aspirin should be monitored over time and their treatment changed to warfarin if risk factors emerge; this occurs in 10%-15% of patients being treated with aspirin per year.21 Who to treat with warfarin Warfarin is indicated for individuals with chronic AF who are at high absolute risk of stroke (> 4% per year), such as those with any of the independent thromboembolic risk factors listed above, and a lower risk of haemorrhage (E1) (see Box 2). Similarly, anticoagulant therapy should also be considered in patients with paroxysmal AF, again depending on the thromboembolic risk factors (Box 2) as well as the frequency and duration of the paroxysms. Although clinical trial evidence suggests the stroke rate of patients with paroxysmal AF is similar to that of patients with chronic AF,26 the trials did not specifically examine the benefits of antithrombotic therapy in patients with paroxysmal AF. Furthermore, the range of thromboembolic risk in such patients is likely to be extremely wide, from very low for patients who have one short paroxysm once a year to considerably higher for patients who have daily lengthy paroxysms. What is the optimal target INR? The intensity of oral anticoagulant therapy that provides the best balance between the prevention of thromboembolism and the occurrence of bleeding complications appears to be an INR of between 2.0 and 3.0, but may be lower (INR, 1.8 to 2.0) in patients at greater risk of bleeding (eg, the elderly), and may be higher in patients at greater risk of thromboembolism, such as those with prosthetic heart valves [INR, 3.0-4.0]) (E32).47,48It is important to emphasise that, in people in whom anticoagulant therapy is indicated, the risk of stroke increases substantially when the INR falls below 2.0. Patients with an INR of 1.7 have twice the odds of stroke (95% CI, 1.6-2.4 times), and those with an INR of 1.5 have 3.3 times the odds of stroke (95% CI, 2.4-4.6 times) as those with an INR of 2.047 (E32). What if warfarin therapy needs to be ceased? When cessation of warfarin therapy is required because of other (usually surgical) procedures, it is necessary to stratify the invasiveness of the procedure (minimal versus major) and the short-term risk of thromboembolism. Warfarin can be discontinued for five days before a major procedure and continued at a decreased dose for a minor procedure. Therapy should be reinstituted as soon as possible after invasive procedures. Patients at high risk of thromboembolism (eg, severe mitral stenosis, mechanical mitral prosthesis, left ventricular dysfunction) should be admitted to hospital early for intravenous administration of heparin during warfarin cessation. References Lake FR, Cullen KJ, de Klerk NH, et al. Atrial fibrillation and mortality in an elderly population. Aust N Z J Med 1989; 19: 321-326. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988. National Health and Medical Research Council. A guide to the development, implementation, and evaluation of clinical practice guidelines. Canberra: NHMRC, 1999. Kilborn MJ. Atrial fibrillation. Med J Aust 1999; 170: 498-504. Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. Ann Intern Med 1987; 106: 503-506. Stoddard MF. Risk of thromboembolism in new onset or transient atrial fibrillation. Prog Cardiovasc Dis 1996; 39: 69-80. Laupacis A, Albers G, Dalen J, et al. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 (5 Suppl): 579S-589S. Klein AL, Grimm RA, Black IW, et al. Cardioversion guided by transesophageal echocardiography: The ACUTE Pilot Study. A randomised, controlled trial. Ann Intern Med 1997; 126: 200-209. Bashir M, Grimm RA, Jaber WA, et al. Elderly patients do not have an excessive risk for complications or recurrence following transoesophageal echocardiography-guided cardioversion of atrial arrhythmias: results from the ACUTE registry. J Am Coll Cardiol 2000; 35 (Suppl A): 119A (abstract no. 1097-73). Catherwood E, Fitzpatrick WD, Greenberg ML, et al. Cost-effectiveness of cardioversion and anti-arrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med 1999; 130: 625-636. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000; 342: 913-920. Resnekov L. Present status of electroversion in the management of cardiac dysrhythmias. Circulation 1973; 47: 1356-1363. Lown B, Perlroth MG, Kaidbey S, et al. "Cardioversion" of atrial fibrillation: a report on the treatment of 65 episodes in 50 patients. N Engl J Med 1963; 269: 325-331. Manning WJ, Silverman DI, Gordon SPF, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328: 750-755. Petersen P, Boysen G, Godfredsen J, et al. Placebo-controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet 1988; i: 175-179. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990; 323: 1505-1511. Stroke prevention in atrial fibrillation study: final results. Circulation 1991; 84: 527-539. Connolly SJ, Laupacis A, Gent M, et al, for the CAFA Study Coinvestigators. Canadian atrial fibrillation anticoagulation (CAFA) study. J Am Coll Cardiol 1991; 18: 349-355. Ezekowitz MD, Bridgers SL, James KE, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) Investigators. Warfarin in the prevention of stroke associated with atrial fibrillation. N Engl J Med 1992; 327: 1406-1412. Secondary prevention in nonrheumatic atrial fibrillation and transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993; 342: 1255-1262. Warfarin versus aspirin for the prevention of thrombo-embolism in atrial fibrillation. Stroke prevention in atrial fibrillation II study. Lancet 1994; 343: 687-691. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high risk patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638. Gullov AL, Koefoed BG, Petersen P, et al. Mini-dose warfarin and aspirin in atrial fibrillation. Second Copenhagen Atrial Fibrillation Aspirin and Anticoagulation Study (AFASAK 2). Arch Intern Med 1998; 158: 1513-1521. Vermeer F, Langenberg M, Hellemons BS, et al. Primary prevention of arterial thrombo-embolism in non-rheumatic atrial fibrillation: results of the PATAF study. Eur Heart J 1998; 19 (Abstract Suppl): 154. Pengo V, Zasso A, Barberi F, et al. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998; 82: 433-437. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomised controlled trials. Arch Intern Med 1994; 154: 1449-1457. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial haemorrhage. Facts and hypotheses. Stroke 1995; 26: 1471-1477. Gallus AS, Baker RI, Chong BH, et al, on behalf of the Australasian Society of Thrombosis and Haemostasis. Consensus guidelines for warfarin therapy. Recommendations from the Australasian Society of Thrombosis and Haemostasis. Med J Aust 2000; 172: 600-605. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205-1210. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349: 1569-1581. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999; 131: 492-501. Collaborative overview of randomised trials of anti platelet therapy. I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994; 308: 81-106. Peverill RE. Warfarin or aspirin: both or others? Med J Aust 1999; 171: 321-326. Morocutti C, Amabile G, Fattapposta F, et al, for the SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. Stroke 1997; 28: 1015-1021. Predictors of thromboembolism in atrial fibrillation: clinical features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116: 1-5. Predictors of thromboembolism in atrial fibrillation: echocardiographic features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116: 6-12. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation. A prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998; 158: 1316-1320. Fatkin D, Feneley M. Stratification of thromboembolic risk of atrial fibrillation by transthoracic echocardiography: the relative role of left atrial appendage function, mitral valve disease, and spontaneous echo contrast. Prog Cardiovasc Dis 1996; 39: 57-68. Jones EF, Calafiore P, McNeil J, et al. Atrial fibrillation with left atrial spontaneous contrast detected by transoesophageal echocardiography is a potent risk factor for stroke. Am J Cardiol 1996; 78: 425-429. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996; 156: 409-416. A randomised trial of anticoagulants versus aspirin after cerebral ischaemia of presumed arterial origin. The Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) Study Group. Ann Neurol 1997, 42: 857-865. Man-Son-Hing M, Laupacis A, O'Connor A, Wells G. Warfarin for atrial fibrillation: the patient perspective. Arch Intern Med 1996; 156: 1841-1848. Gage BF, Cardinalli AB, Owens DK. Cost-effectiveness of preference-based antithrombotic therapy for patients with nonvalvular atrial fibrillation. Stroke 1998; 29: 1083-1091. Thomson R, Parkin D, Eccles M, et al. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation. Lancet 2000; 355: 956-962. Kopecky SL, Gersh BJ, McGoon MD. The natural history of lone atrial fibrillation: a population-based study over three decades. N Engl J Med 1987; 317: 669-674. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke. A meta-analysis of randomised controlled trials. JAMA 1998; 280: 1930-1935. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-546. Cannegieter SC, Rosendal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17. Background and evidence basis of recommendations The National Heart Foundation (NHF) Consensus Guidelines for Non-valvular Atrial Fibrillation and Stroke Prevention were written by Clinical Associate Professor Graeme J Hankey on behalf of the National Blood Pressure Advisory Committee of the NHF, which comprises Professor L Wing (chair), Dr A Boyden, Dr A Dart, Dr K Duggan, Clinical Associate Professor G Hankey, Dr M Nelson, Professor I Puddey, Dr M Stowasser, and Dr J Vial. The draft guidelines were circulated for comment to the above members of the committee, who have clinical and research expertise or interests in hypertension, atrial fibrillation, and stroke prevention. Comment was also sought from the Medical Director of the Heart Foundation, Professor Andrew Tonkin. All comments were incorporated into the final document, which was ratified by the Heart Foundation's Cardiovascular Health Advisory Committee. All available evidence from controlled experimental and observational studies was combined with clinical experience to provide recommendations according to the National Health and Medical Research Council Quality of Evidence ratings.3 Authors' details National Heart Foundation of Australia, Melbourne, VIC. Graeme J Hankey, MD, FRACP, Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital, Perth, WA, and Clinical Associate Professor, Department of Medicine, University of Western Australia. Reprints will not be available from the author. Correspondence: Clinical Associate Professor G J Hankey, Stroke Unit, Royal Perth Hospital, Wellington Street, Perth, WA 6001. gjhankeyATcyllene.uwa.edu.au * L Wing (chair), A Boyden, A Dart, K Duggan, M Nelson, I Puddey, M Stowasser, J Vial 1: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system3 for assessing the level of evidence: E1 Level I Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2 Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group. E33 Level III-3 Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV Evidence obtained from case-series, either post-test, or pretest and post-test. Back to text 2: Risk stratification and prophylaxis in atrial fibrillation High risk (6%-12% per year risk of stroke) Age >65 years and hypertension or diabetes Previous transient ischaemic attack (TIA) or stroke Valvular heart disease o Heart failure Recent myocardial infarction Impaired left ventricular function on echocardiography Thyroid disease o Left atrial thrombus or left atrial spontaneous echo contrast (TOE done on basis of clinical suspicion) Treatment: Warfarin (target INR 2.0-3.0) if possible and not contraindicated. Moderate risk (2%-5% per year risk of stroke) Age 65 years and hypertension or diabetes Age >65 years and not in high risk group Treatment: Warfarin (target INR 2.0-3.0) or aspirin 75-300mg daily, depending on individual case and echocardiography findings. Low risk (≤1% per year risk of stroke) Age 65 and no hypertension, diabetes, TIA, stroke, or other clinical risk factors Treatment: None, or aspirin 75-300mg daily. Back to text

Graeme J Hankey

Snapshots A new kind of cave painting MJA 2000; 173: 658 This photograph confirms that Indigenous Australians were in the distal oesophagus well before European settlement. The photograph was taken at upper gastrointestinal endoscopy. It shows a segment of Barrett's epithelium (dark pink) just above the lower oesophageal sphincter. The lighter pink areas are residual islands of squamous epithelium. The "hand print" reminded me of Indigenous cave paintings in the outback. Brian Jones, FRACP Hornsby, NSW

Brian Jones

Notable Cases Non-alcoholic steatohepatitis in children and adolescents Nicholas D Manton, Jill Lipsett, David J Moore, Geoffrey P Davidson Anthony J Bourne and Richard T L Couper MJA 2000; 173: 476-479 We describe 17 children with non-alcoholic steatohepatitis. All had elevated levels of serum liver enzymes and 16 were morbidly obese. Liver biopsy showed variable steatosis and fibrosis in nine patients. At follow-up, 12 of 14 patients had persistent morbid obesity and 11 had elevated liver enzyme levels. Methods - Clinical findings - Discussion - References - Authors' details - - More articles on Gastroenterology Non-alcoholic steatohepatitis (NASH) is well recognised in adults. It occurs with obesity, insulin resistance or insufficiency and associated metabolic abnormalities such as hyperlipidaemia and hyperglycaemia. NASH also occurs in childhood, but, in this group, it is not as well characterised. Obese, prepubertal children are at risk of liver disease, with liver biopsies showing fatty change, inflammation and fibrosis with progression to necrosis and cirrhosis.1-4We report here selected features of NASH in children presenting to a tertiary care child and adolescent hospital. We aimed to determine: the demographic details of these children; the presenting clinical signs and symptoms, and any associated conditions; the biochemical and radiological findings; the range of histopathological findings with liver biopsy; and the clinical and biochemical outcomes. Methods Patient identification Patients were retrospectively identified by searching a computerised database of histopathological specimens at the Women's and Children's Hospital (formerly the Adelaide Children's Hospital) for the years 1972-1999. All liver biopsies in this period were reviewed, and cases selected if the liver biopsy showed steatosis. Clinical details, investigations and disease course were determined (retrospectively) from the hospital records. The patients' weight/ideal body weight ratios were calculated using charts from the National Centre for Health Statistics Growth Curves for Children.5 Exclusion criteria Patients were excluded when a known cause of steatosis was present. These included inborn errors of metabolism, viral hepatitis, autoimmune hepatitis, total parenteral nutrition, cystic fibrosis or Wilson's disease. Liver biopsies Fatty change was described as macrovesicular or microvesicular, and the extent of steatosis was graded as mild, moderate or severe. The presence of inflammation was graded as mild, moderate or severe. Fibrosis was described (eg, portal tract fibrosis, perisinusoidal fibrosis, septal fibrosis, bridging fibrosis, cirrhosis). In all cases, tissue was submitted for electron microscopy. Clinical findings Seventeen patients were identified: 11 males and six females. Most (14 of 17) were identified in the past five years. Mean age ± SD was 11.7 ± 1.7 years (range, 9-15 years). Persisting intermittent abdominal pain (10 patients) was the commonest presenting symptom. Two patients were identified after hepatomegaly on review for known insulin dependent diabetes mellitus (IDDM) and, in two patients, abnormal liver function tests (LFTs) were detected incidentally during investigation for apparently unrelated problems (seizure and diarrhoeal illness). One patient (Patient 17) was asymptomatic and was investigated because his twin brother (Patient 13) was found to have NASH. Five patients had relevant family history: one had parents and brother with morbid obesity; one had a family history of Gilbert disease, a disorder of bilirubin conjugation; one had a father with cirrhosis; and two were twins with obesity and abnormal liver function test results. Box 1 summarises the clinical, biochemical and radiological findings for our patients. Sixteen of the 17 patients were morbidly obese (> 24% over ideal body weight [IBW]; mean, 53%; range, 25% to 118% over IBW). Eight patients had hepatomegaly either on clinical or ultrasound examination. Alanine aminotransferase (ALT) was elevated in all patients, gamma glutamyl transferase (GGT) was elevated in eight, and alkaline phosphatase (ALP) was normal in all patients. Five patients had elevated triglyceride levels and two had elevated total serum cholesterol levels. Ultrasound examination in 11 patients showed increased echogenicity (suggestive of increased liver fat) in 10. The liver biopsy changes included both macro- and microvesicular steatosis. Inflammation was present in eight patients and fibrosis was present in nine patients. The degree of fibrosis ranged from mild portal tract fibrosis to bridging fibrosis to probable cirrhosis (as identified in a repeat biopsy in one of the patients). Increased glycogen (intracellular and intranuclear) was seen in the two patients with known IDDM and a third patient in whom a subsequent diagnosis of IDDM was made. Mallory's hyalin was not seen in any of the cases on immunohistochemical staining, a noteworthy finding given that Mallory bodies are said to be seen more commonly in alcoholic steatohepatitis than in NASH.5 Box 2 shows the follow-up data. Eleven patients had continued elevation of liver enzyme levels, and persistent obesity despite counselling. Two of the obese patients had normalisation of LFTs with weight loss. None of the other obese patients lost weight, and in these patients liver enzyme levels remained elevated. One of the patients with diabetes (the only patient who was not morbidly obese) had normalisation of LFTs with improved diabetes control. Seven of the more recently identified patients were treated with ursodeoxycholic acid; one had normalisation of LFTs with weight loss. Discussion The association of abnormalities in liver function and morphological changes on liver biopsy (steatosis, inflammation and/or fibrosis) with obesity and insulin resistance/insufficiency is well established in adults and becoming increasingly recognised in children. Most cases of NASH in the paediatric age group have been described in older children and adolescents.1,2 Our series of 17 patients shows that children may be asymptomatic or present with vague, non-specific complaints, which conform to those described previously.6 One of our patients had marked acanthosis nigricans, a finding indicative of insulin resistance and reported recently in another study.2 Most of our patients were identified over the past 5-7 years, and we believe this is largely due to the increased awareness of this condition and the increasing prevalence of obesity in children in Australian society.7 Clinical findings In our series, all but one of the patients who had ultrasound of the liver showed variable enlargement and increased echogenicity, consistent with fatty change. In a study of 72 obese children,4 increased echogenicity was found in 53% of cases, and the authors proposed ultrasound as a useful tool to determine liver involvement in obese children. Certainly, our experience agrees with this. However, liver ultrasound will not detect the more subtle histopathological features of more severe liver damage, such as fibrosis. Only liver biopsy can demonstrate such abnormalities. Elevated ALT and GGT levels were the most common findings with LFTs. This is consistent with another study,4 in which ALT was the most elevated enzyme and the ALT/AST ratio was the reverse of that seen in alcoholic steatohepatitis. We found no correlation between presenting signs and symptoms, LFT abnormalities, and the morphological changes at liver biopsy, unlike those reported in adult patients with NASH.8 Liver histology We found a wide variation in biopsy findings, from steatosis alone to steatohepatitis and mild fibrosis to probable cirrhosis (with documented progression on repeat biopsy). In the patients with known glucose intolerance, increased glycogen within hepatocyte cytoplasm and nuclei was noted. In addition, in Patient 1 (where increased glycogen was noted), IDDM was subsequently diagnosed. In adults, NASH follows a relatively benign clinical course compared with alcoholic steatohepatitis.8,9 Although follow-up data in the paediatric age group are limited, the finding of evolving cirrhosis in one of our patients highlights the view that NASH may be a progressive disease.10-12 Rashid and Roberts have speculated that at least some patients with cryptogenic cirrhosis occurring in adulthood may have had NASH since childhood.2 A recent study13 found that NASH is under-recognised in many adults with so-called cryptogenic cirrhosis (with as many as 74% of such patients having a history of obesity or diabetes mellitus). Septal fibrosis occurs frequently in overweight adult patients with abnormal LFTs.14 Pathogenesis The pathogenesis of NASH is still being determined. A recent study15 based on data from the National Health and Nutrition Examination Survey concluded that reduced serum levels of fat-soluble antioxidants are present in obese children. Oxidant stress injury may be pivotal in the pathogenesis of NASH,16 resulting in adipose tissue synthesis of tumour necrosis factor (TNF). TNF antagonises insulin receptors, leading to glucose intolerance, hyperlipidaemia and steatosis. Another study17 suggests that fatty livers are vulnerable to liver ATP depletion and necrosis, indicating that altered hepatic energy homoeostasis may be involved. Increased lipid peroxidation may increase hepatic stellate cell activation.18 Activated stellate cells are matrix-producing myofibroblast-like cells which are thought to be responsible for the laying down of fibrous tissue in hepatic fibrosis.18 Intervention At this stage, therapy is limited to weight control and treatment of insulin lack or resistance. Although weight loss in adult patients has been effective in leading to regression of fatty change,19 in all but two of our obese patients weight control was not achieved and abnormalities of liver function persisted. Seven of our patients were treated with ursodeoxycholic acid, and one showed normalisation of LFTs (with weight loss). Ursodeoxycholic acid improves LFTs in patients with NASH.20 It is thought that this agent is cytoprotective and, by preventing membrane injury, may reduce liver injury in NASH.20 In our institution, treatment of NASH with ursodeoxycholic acid is largely a matter of individual preference for treating physicians, and guidelines have not been established. Recommendations Children presenting to paediatric outpatient units who are morbidly obese should have their LFTs measured, and should be counselled regarding weight loss. If the baseline LFTs are elevated, the measurements should be repeated in 3-4 months. If the LFTs are still abnormal, then other investigations (including hepatitis B and C virus serology, autoimmune antibody screen, caeruloplasmin levels, and serum triglyceride, cholesterol and blood sugar levels) should be performed and liver biopsy considered. Liver biopsy and other investigations might be performed earlier if the liver enzyme levels are grossly elevated. References Baldridge AD, Perez-Atayde AR, Graeme-Cook F, et al. Idiopathic steatohepatitis in childhood: a multicentre retrospective study. J Pediatr 1995; 127: 700-704. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000; 30: 48-53. Ludwig J, McGill DB, Lindor KD. Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997; 12: 398-403. Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 1997; 42: 1428-1432. National Centre for Health Statistics Growth Curves for Children. Adapted from Hamill PVV: NHCS Growth Curves for Children. DHEW Publication (PHS) 78-1650. Neuschwander-Tetri B, Bacon B. Nonalcoholic steatohepatitis. Med Clin N Am 1996; 80: 1147-1165. Lazarus R, Wake M, Hesketh K, Waters E. Change in body mass index in Australian primary school children, 1985-1997. Int J Obes Relat Metab Disord 2000; 24: 679-684. Lee R. Nonalcoholic steatohepatitis, a study of 49 patients. Hum Pathol 1989; 20: 594-598. Mohd R, James O, Burt A, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714-1719. Bacon B, Farakvash M, Janney C, Neuschwander-Tetri B. Nonalcoholic steatohepatitis: tightening the morphological screws on a hepatic rambler. Hepatology 1995; 21: 1742-1743. Propst A, Propst T, Judmaier G, Vogel W. Prognosis in nonalcoholic steatohepatitis [letter]. Gastroenterology 1995; 108: 1607. Kim W, Poterucha J, Porayko M, et al. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 1996; 62: 1802-1805. Caldwell S, Oelsner D, Iezzoni J, et al. Cryptogenic cirrhosis: clinical characterisation and risk factors for underlying disease. Hepatology 1999; 29: 664-669. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 1117-1123. Strauss R. Comparison of serum concentrations of α-tocopherol and β-carotene in a cross-sectional sample of obese and nonobese children (NHANES III). J Pediatr 1999; 134: 160-165. Lavine J. Relative antioxidant deficiency in obese children: a weighty contributor to morbidity? [editorial]. J Pediatr 1999; 134: 132-133. Cortez-Pinto H, Chatham J, Chacko VP, et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282: 1659-1664. Reeves H, Burt A, Wood S, Day C. Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis. J Hepatol 1996; 25: 677-683. Lieverse R, Jansen J, Masclee A, Lamers C. Gastrointestinal disturbances with obesity. Scand J Gastroenterol 1993; 200: S53-S58. Laurin J, Lindnor K, Crippin J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-1467. (Received 3 Apr, accepted 3 Aug, 2000) Authors' details Women's and Children's Hospital, Adelaide, SA. Nicholas D Manton, MB BS, Registrar, Department of Histopathology; Jill Lipsett, PhD, FRCPA, Histopathologist, Department of Histopathology; David J Moore, MB BS, FRACP, Paediatric Gastroenterologist, Department of Gastroenterology; Geoffrey P Davidson, MD, FRACP, Director, Department of Gastroenterology; Anthony J Bourne, MB BS, FRACPA, Director, Department of Histopathology; Richard T L Couper, MB ChB, FRACP, Paediatric Gastroenterologist, Department of Gastroenterology, and University of Adelaide Department of Paediatrics. Reprints will not be available from the authors. Correspondence: Dr R T L Couper, University of Adelaide Department of Paediatrics and Department of Paediatric Gastroenterology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006. rcouperATmedicine.adelaide.edu.au Make a comment 1: Clinical and investigation findings Patient Examination Biochemistry* Ultrasound Liver biopsy 1 (M, 13)† 27% over IBW acanthosis nigricans ALT ratio 3.2 GGT ratio 4.4 AST ratio 1.9 Enlarged EL Severe macrovesicular steatosis with increased glycogen 2 (F, 13) 27% over IBW short stature, hepatomegaly ALT 3.2 GGT 1.1 AST 3.0 Enlarged EL Moderate macro- and microvesicular steatosis with increased glycogen and moderate inflammation 3 (F, 11) 118% over IBW ALT 1.3 GGT 5.5 Normal Severe macro- and microvesicular steatosis 4 (F, 9) 45% over IBW ALT 2.2 nd Severe macrovesicular steatosis, mild portal tract inflammation, mild portal tract fibrosis 5 (M, 12) 10% over IBW tender hepatomegaly ALT 11.3 GGT 5.1 Enlarged EL Moderate macro- and microvesicular steatosis, scattered glycogenated nuclei 6 (M, 11) 115% over IBW ALT 3.2 GGT 1.6 AST 1.6 Fatty change Severe mixed macro- and microvesicular steatosis with bridging fibrosis and evolving cirrhosis 7 (M, 13) 81% over IBW hepatomegaly ALT 1.2 nd Moderate macrovesicular steatosis, mild portal tract inflammation 8 (M, 14) 74% over IBW ALT 16.0 GGT 4.9 EL Severe macrovesicular steatosis, mild septal fibrosis 9 (M, 15) 88% over IBW ALT 2.5 AST 1.5 TG 1.8 EL Severe macrovesicular steatosis, minimal perisinusoidal fibrosis 10 (F, 10) 32% over IBW ALT 20.7 GGT 1.4 Cholesterol 1.2 nd Moderate macro- and microvesicular steatosis, mild portal tract inflammation 11 (M, 13) 60% over IBW mild abdominal tenderness ALT 1.3 GGT 1.1 TG 1.5 nd Mild macrovesicular steatosis 12 (M, 11) 55% over IBW enlarged liver ALT 1.6 TG 1.7 EL Moderate macro- and microvesicular steatosis, moderate portal tract inflammation, portal tract fibrosis with bridging 13‡ (M, 12) 37% over IBW ALT 2.2 EL Moderate macro- and microvesicular steatosis, mild perisinusoidal fibrosis 14 (F, 9) 44% over IBW palpable liver edge ALT 3.6 nd Moderate macrovesicular steatosis, focal hepatocyte necrosis, mild portal tract inflammation, mild perisinusoidal fibrosis 15 (F, 10) 26% over IBW palpable liver edge ALT 2.8 Cholesterol 1.2 EL Mild macrovesicular steatosis, mild portal tract inflammation 16 (M, 11) 25% over IBW palpable liver edge ALT 4.7 TG 1.1 EL Severe macro- and microvesicular steatosis, mild portal tract inflammation, portal tract fibrosis with early bridging 17‡ (M, 12) 37% over IBW ALT 4.8 TG 1.3 nd Severe macrovesicular steatosis, mild portal tract fibrosis with early bridging *Biochemistry results are given as a ratio of the measured value of serum liver enzyme, serum triglyeride, or serum cholesterol levels over the normal maximum for the particular method used. †Sex and age at presentation. ‡Twins. IBW=ideal body weight. ALT=alanine aminotransferase. GGT=gamma glutamyl transferase. AST=aspartate aminotransferase. TG=Serum triglycerides. EL=echogenic liver. nd=not done. Back to text 2: Outcome data at latest follow-up Patient Follow-up period Percentage over IBW Biochemistry* Remarks 1 6 years 45% ALT 1.9 GGT 5.8 Subsequently diagnosed with IDDM and Alstrom syndrome 2 Lost to follow-up 3 6 years 25% Rapid weight loss with puberty, normalisation of LFTs 4 15 months 36% ALT 3.4 5 2.5 years 8% Normalisation of LFTs with improved diabetes control 6 2.5 years 60% ALT 1.7 Persisting obesity with some improvement in LFTs. Treated with ursodeoxycholic acid. Follow-up liver biopsy showed probable cirrhosis 7 Lost to follow-up 8 2 years 78% ALT 4.1 GGT 1.9 Treated with ursodeoxycholic acid 9 1 year 51% ALT 4.0 10 4 months 30% ALT 8.0 GGT 2.0 11 1 year 56% ALT 2.3 GGT 1.4 12 1 year 57% ALT 7.9 GGT 2.2 13† 15 months 36% ALT 3.0 Treated with ursodeoxycholic acid 14 14 months 36% ALT 3.8 Treated with ursodeoxycholic acid 15 Not yet reviewed 16 1 year 15% Normalisation of LFTs with weight loss. Treated with ursodeoxycholic acid 17† 1 year 45% ALT 2.9 Treated with ursodeoxycholic acid *Biochemistry results are given as ratio of the measured value of serum liver enzyme levels and the normal maximum for the method used. †Twins. LFT=liver function test. ALT=alanine aminotransferase. GGT=gamma glutamyl transferase. Back to text

Nicholas D Manton · Jill Lipsett · David J Moore · Geoffrey P Davidson · Anthony J Bourne

Editorial Virtually viewing the large bowel: the future of colorectal cancer screening? New technologies add to the debate over how best to screen for colorectal cancer MJA 2000; 172: 416-417 Colorectal cancer is a disease ideal for screening: it is common; prognosis is poor if it is detected late but excellent if it is treated early; and there is a premalignant phase (the adenoma) which has a relatively long dwell time during which it can be detected and treated relatively safely. In addition, higher-than-average-risk groups can be identified and targeted. It has been recommended that a colorectal cancer screening program be established in Australia, but, because of uncertainties about the program's feasibility, that this be implemented through a series of pilot studies.1 Nonetheless, for asymptomatic individuals aged over 50 years without a family history of colorectal cancer, the National Health and Medical Research Council favours screening by annual faecal occult blood testing (FOBT), complemented by flexible sigmoidoscopy every five years.2The problem is that all current screening tools are imperfect. FOBT is most widely advocated as the only test shown to reduce mortality from colorectal cancer (by 15%-33%) when used for mass population screening.1 It is also cheap, safe and can be administered by the general practitioner. Accuracy depends on the type of FOBT used and the frequency of testing, but, on an individual basis, FOBT misses between 21% and 63% of cancers and most adenomas, and has a false-positive rate of 2%-13%.3 Flexible sigmoidoscopy is under trial both in Australia and overseas as a tool for population screening. The rationale is that most neoplasms occur within reach of the flexible sigmoidoscope, and that distal adenomas may be predictors of proximal lesions. In this issue of the Journal, Nicholson and colleagues4 show, as have others,5 that, among screened subjects with adenomas, 25% have proximal adenomas only (defined by Nicholson et al as proximal to the splenic flexure). These are beyond the reach of flexible sigmoidoscopy. This study illustrates one of the problems of flexible sigmoidoscopy screening -- accuracy for cancer and polyp detection. However, other important issues must be considered in assessing a screening test, such as acceptability, compliance, availability, safety and cost. Indeed, in the Australian context, initial participation rates in flexible sigmoidoscopy screening have been disappointing (12%),6 although recent data indicate that these rates have increased to around 40% (Associate Professor John Olynyk, Department of Gastroenterology, Fremantle Hospital, Fremantle, WA, personal communication). The findings of Nicholson and colleagues support the need for imaging the whole colon in colorectal neoplasm screening. Methods advocated for this include double-contrast barium enema and colonoscopy. Both have their supporters. However, data on use of these methods for population screening of average-risk individuals are limited, and both have drawbacks that make them unlikely to be widely accepted for mass screening. Setting aside considerations of compliance, double-contrast barium enema is probably not sufficiently accurate without concomitant flexible sigmoidoscopy (which would increase costs and almost certainly decrease compliance), and imposes a significant radiation dose. Total colonoscopy has the advantages of accuracy and ability to combine screening with therapy (polypectomy) but carries a small but significant risk.7 A certain level of competence is required to achieve adequate rates of caecal intubation, and, although it is difficult to determine exact completion rates, outside specialist centres they may be only 80%-90%8,9 or less. Taking into account the need for sedation, consequent bed fees and cost of time off work, colonoscopy is relatively expensive. A recent contender for screening is virtual colonoscopy (computed tomography [CT] colography). After bowel preparation, the colon is insufflated with air or carbon dioxide, and a spiral CT scan performed, preferably in supine and prone positions. Because of the volumetric nature of data acquisition, sagittal and coronal reformatted images can be viewed, as well as the source axial images, and endoluminal images can be reconstructed, simulating an endoscopic view. Navigation using these images can be achieved by manual manoeuvres or "fly-through" techniques that automatically centre on the bowel lumen. While not yet as accurate as colonoscopy for polyp detection, virtual colonoscopy is likely to become significantly more accurate with expected developments in hardware and software. Currently, virtual colonoscopy is more accurate than FOBT and can probably compete with flexible sigmoidoscopy with regard to larger polyps. A study from Boston has reported sensitivities of 91%, 82% and 55% for polyps of diameter 10 mm or more, 6-9 mm, and 5 mm or less, respectively.10 Virtual colonoscopy also has several potential advantages as a screening tool: it is minimally invasive and quick for the patient (the scan takes only a few minutes); no sedation is required; and initial studies have shown that it is highly acceptable to patients.11 Its "high-tech", virtual reality profile makes it potentially attractive to the lay public. While using ionising radiation, dosages are considerably less than for double-contrast barium enema when low-dosage protocols are used. Using the current scanning protocol in our institution, total effective radiation dose has been calculated to be less than 5 mSv, even when supine and prone scans are performed (compared with about 8 mSv for conventional double-contrast barium enema). In addition, early studies hold out the possibility that magnetic-resonance (MR) virtual colonoscopy may eventually supersede CT virtual colonoscopy, eliminating ionising radiation.12 Lastly, there is the potential to detect incidental extracolonic disease, such as asymptomatic aortic aneurysms and renal carcinoma. Problems currently limiting the application of virtual colonoscopy as a screening tool include its lack of sensitivity for small polyps, particularly those 5 mm or less in diameter.10 Does this matter in the context of a screening program? Probably not: the chances of a 5 mm lesion being malignant are negligible; if screening takes place every five years the dwell time for such a small lesion allows an enlarging lesion to be picked up on subsequent examinations. A further limitation is the need for bowel preparation, which is likely to be a significant factor in reducing participation rates. However, the use of faecal tagging to allow software to differentiate faeces and polyps may eventually minimise, or even eliminate, the need for bowel preparation. In addition, other factors, such as availability, operator experience and cost, need to be evaluated in assessing the potential role of virtual colonoscopy as a screening tool for colorectal cancer. Much of the present cost is related to the time required for image processing and reading of the images by the radiologist, which is as long as 30-45 minutes with current commercially available technology. However, this time will inevitably be reduced significantly by further technological advances, such as faster computer processing and automated polyp detection software. Finally, it would be preferable that images are read promptly so that individuals with abnormalities have the opportunity of proceeding to same-day colonoscopy to avoid the need for a second bowel preparation. So, is virtual colonoscopy a viable option as a screening tool for colorectal cancer in the average-risk individual? There is little doubt that, in its current state of development, it is not ready for widespread use. In addition to the limitations already discussed, the excellent sensitivity data reported by some centres10,13 have not been widely replicated.14 Equally, there is a high probability that, at its rate of evolution, in the not-too-distant future CT (or MR) virtual colonoscopy will become an accepted (or even the accepted) modality for colorectal cancer screening. In the meantime, while waiting for the technology to catch up, feasibility studies of virtual colonoscopy are needed to examine issues such as participation rates, factors affecting recruitment into screening programs, acceptability and cost. Richard M Mendelson Radiologist Geoffrey M Forbes Gastroenterologist, and Clinical Senior Lecturer University of Western Australia, Royal Perth Hospital, WA Disclosure statement: The authors are active in clinical research into virtual colonoscopy and are planning a feasibility study of the technique in colorectal cancer screening. Australian Health Technology Advisory Committee. Colorectal cancer screening. Canberra: AGPS, 1997. National Health and Medical Research Council. Guidelines for the prevention, early detection and management of colorectal cancer. Canberra: NHMRC, 1999. Allison JE, Tekawa IS, Ransom LJ, Adrain AL. A comparison of fecal occult blood tests for colorectal-cancer screening. N Engl J Med 1996; 334: 155-159. Nicholson FB, Korman MG, Stern AI, Hansky J. Distribution of colorectal adenomas: implications for bowel cancer screening. Med J Aust 2000; 172: 428-430. Kadakia SC, Wrobleski CS, Kadakia AS, Meier NJ. Prevalence of proximal colonic polyps in average-risk asymptomatic patients with negative fecal occult blood tests and flexible sigmoidoscopy. Gastrointest Endosc 1996; 44: 112-117. Olynyk JK, Aquilia S, Fletcher DR, Dickinson JA. Flexible sigmoidoscopy screening for colorectal cancer in average-risk subjects: a community-based pilot project. Med J Aust 1996; 165: 74-76. Waye J, Kahn O, Auerbach M. Complications of colonoscopy and flexible sigmoidoscopy. Gastrointest Endosc Clin N Am 1996; 6: 343-377. Thiis-Evensen E, Hoff GS, Sauar J, et al. Flexible sigmoidoscopy or colonoscopy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of normal population aged 63 to 72 years. Gut 1999; 45: 834-839. Freeman B, Engel JJ, Fine MS, DiVita DP. Colonoscopy to the cecum: How often do we get there? Experience in a community hospital. Am J Gastroenterol 1993; 88: 789. Fenlon HM, Nunes DP, Schroy P, et al. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 1999; 341: 1496-1503. Forbes GM, Mendelson RM. Patient acceptance of virtual colonoscopy [letter]. Endoscopy 2000; 32: 274. Debatin JF, Luboldt W, Bauerfeind P. Virtual colonoscopy in 1999: computed tomography or magnetic resonance imaging? Endoscopy 1999; 31: 174-179. Kay CL, Kulling D, Hawes RH, et al. Virtual endoscopy -- comparison with colonoscopy in the detection of space-occupying lesions of the colon. Endoscopy 2000; 32: 226-232. Rex DK, Vining D, Kopecky KK. An initial experience with screening for colon polyps using spiral CT with and without CT colography (virtual colonoscopy). Gastrointest Endosc 1999; 50: 309-313. Make a comment

Richard M Mendelson · Geoffrey M Forbes

Healthcare Distribution of colorectal adenomas: implications for bowel cancer screening Fiona B Nicholson, Melvyn G Korman, Anthony I Stern and Jack Hansky MJA 2000; 172: 428-430 For editorial comment, see Mendelson & Forbes Abstract - Methods - Results - Discussion - References - Authors' details - - More articles on Oncology Abstract Objective: To determine the distribution of colorectal adenomas relative to the splenic flexure in an asymptomatic population undergoing colonoscopy, as an indicator of the number of patients with adenomas who would be missed by screening with flexible sigmoidoscopy. Design: Retrospective survey of medical records. Setting: Private endoscopy centres in Melbourne, Victoria. Subjects: All 1131 asymptomatic individuals who underwent full colonoscopy between 1 January 1995 and 31 December 1997 after referral from a bowel cancer prevention program organised by the endoscopy centres. People referred were aged either 40 years or over with a first-degree relative with bowel cancer, or 50 years or over with marked anxiety about bowel cancer. Main outcome measures: Presence and distribution of colorectal adenomas. Results: Polyps were found in 270 individuals (24%) and were confirmed to be adenomas in 138 (12%). These 138 comprised 106 men and 32 women, with mean age 54 years (range, 40-78 years). Most (86%) had a single adenoma. Position of adenomas in relation to the splenic flexure was: distal only in 85 of the 138 people (62%), proximal only in 34 (25%), and both distal and proximal in 19 (14%). Conclusions: In 25% of asymptomatic people found to have adenomas by this bowel cancer prevention program, the adenomas were found only in the proximal colon, well beyond the reach of the flexible sigmoidoscope. This distribution of adenomas suggests that screening programs cannot rely solely on flexible sigmoidoscopy. Colorectal cancer is the most common internal malignancy in Australia and the second most common cancer overall.1 One in 18 men and one in 27 women will develop this cancer during their lifetime.2 As most colorectal cancers are diagnosed at an advanced stage after symptoms develop, significant improvements in colorectal cancer mortality depend on prevention and early diagnosis. Most colorectal cancers develop from adenomatous polyps.3 If adenomas can be identified and removed, the adenoma-carcinoma sequence is broken, and colorectal cancer may be prevented.4 As adenomas usually cause few, if any, symptoms, they can be detected only by searching for them in asymptomatic individuals. While colonoscopic surveillance programs for detecting adenomas are accepted for those at higher risk of developing colorectal cancer (eg, with a family history),5 screening for the average-risk population remains controversial. In Australia, there are no population-based colorectal cancer screening programs, but the recent report from the Australian Health Technology Advisory Committee suggested pilot programs of faecal occult blood testing (FOBT) alone or in combination with flexible sigmoidoscopy.6 This combination is probably the most accepted method of screening for average-risk colorectal cancer. However, as adenomas and cancers may occur on the right side of the colon, and as not all of these bleed, they could be missed by this combination of tests. In 1991, some private endoscopy centres in Melbourne, Victoria, developed a Bowel Cancer Prevention Program. We aimed to determine how many asymptomatic people who underwent colonosocopy as part of this program had adenomas in the proximal colon only. This would indicate the number of patients with adenomas who would be missed by flexible sigmoidoscopy screening in an Australian population. Methods The study was a retrospective review of patient medical records. Data collection was approved by the Victorian Southern Health Care Network Ethics Committee. Subjects We examined the records of all asymptomatic individuals who underwent full colonoscopy between 1 January 1995 and 31 December 1997 after referral from the Bowel Cancer Prevention Program. Individuals with any symptoms that could be referable to colorectal cancer, such as rectal bleeding, anaemia, change in bowel habit or weight loss, were excluded from the study. The Bowel Cancer Prevention Program targets interested employees of major employer groups or members of participating unions and organisations. Each participant receives educational material about colorectal cancer and is asked to return a simple questionnaire. This assists an expert panel to assess and advise on individual risk of developing colorectal cancer, based on Gut Foundation7 and international guidelines.8 Asymptomatic individuals are referred for colonoscopy if: They are aged 40 years or over and have a self-reported family history of at least one first-degree relative with bowel cancer; or They are aged 50 years or over, and a doctor has requested a colonoscopy for bowel cancer screening because of the patient's marked anxiety. Procedures Informed consent was obtained, and a full colonoscopy was performed with visualisation of the caecum. Adenomas were confirmed by histological examination by private pathology services. Locations of adenomas were noted on the procedure report by the endoscopist at the time of colonoscopy. The position of the splenic flexure, as recognised at colonoscopy, was used to classify adenoma locations as: distal to the splenic flexure only; both distal and proximal to the splenic flexure; and proximal to the splenic flexure only. Data recorded The number of individuals with adenomas and the site of each adenoma within the colon and rectum were recorded, as were complications of sedation or the procedure. Results The records of 1131 asymptomatic individuals who underwent full colonoscopy were examined. The 1131 comprised 715 men and 416 women, with mean age 54 years (range, 40-78 years); 907 (80%) had a family history of colorectal cancer. None of the patients died or required hospitalisation for complications of sedation or the procedure. Colorectal polyps were found in 270 people (24%) and were confirmed to be adenomas in 138 (12%). These 138 comprised 106 men and 32 women, with mean age 54 years (range, 40-78 years). Adenomas were found in 118 of the 907 people with a first-degree relative with bowel cancer (13%) and in 20 of the 224 people whose only risk factor was age 50 years or more (9%). This difference in adenoma rates was statistically significant (P < 0.05). Most of the 138 patients (86%) had a single adenoma, while 14% had two or more. The adenomas ranged from 5 mm to 2 cm in diameter. Distribution of adenomas relative to the splenic flexure is shown in the Box. The distribution did not differ significantly between people who had a family history of colorectal cancer and those who did not: in both groups, 25% had adenomas proximal to the splenic flexure only. Discussion Different regimens are proposed for screening programs to prevent colorectal cancer. These include FOBT, periodic flexible sigmoidoscopy, FOBT combined with flexible sigmoidoscopy, or full colonoscopy. The rationale for a screening sigmoidoscopy is that it would detect most adenomas, as they are most common in the left colon. Further, in those with adenomas (or cancer) proximal to the splenic flexure, the theory is that adenomas would also be found in the distal colon by flexible sigmoidoscopy, thus signalling the need for full colonoscopy -- the concept of the "sentinel" polyp [adenoma].8This theory is not supported by the results of our study. We found that in 25% of asymptomatic individuals with adenomas, the adenomas were found only in the proximal colon, beyond the reach of the flexible sigmoidoscope. This figure is consistent with other studies.9 A sentinel adenoma on the left side signalling proximal adenomas was found in only 14% of people; 62% of subjects had only left-sided adenomas. In our study the distribution of adenomas was assessed from the endoscopists' reports. Experienced endoscopists are correct in determining scope-tip position 83% of the time.10 One cannot assume that a 60 cm flexible sigmoidoscope will reach the splenic flexure. Indeed, a recent report suggests that it reaches 60 cm in only 34% of cases, and far less often in women than in men, with the problem worsening with increasing patient age.11 There are no other Australian data on the incidence or distribution of adenomatous polyps in the colon and rectum. Collett et al showed that distal colorectal cancer or adenomas predicted proximal neoplasia in 30% of subjects, but their study was based on colonoscopy only after a positive result from flexible sigmoidoscopy.12 Their study design did not allow them to accurately determine the distribution of adenomas in the colon and rectum. Colonoscopy remains the final diagnostic pathway for any positive result for a bowel cancer screening test. Some international experts recommend use of colonoscopy as the optimum screening tool to prevent the development of colorectal cancer.13 However, it has not been embraced as the primary screening modality because of concerns about cost, compliance and risk. The risks of colonoscopy include those related to sedation, as well as the procedure, such as perforation (reported at 1 in 200014) and bleeding complicating polypectomy. Complication rates are usually derived from hospital populations, which include many ill patients who have significant comorbidity, and it may be that the risk is considerably less in the far healthier "screening" population. No significant sedation- or procedure-related complications or deaths occurred in our comparatively small series of colonoscopies. The proportion of men to women in the group with the adenomas was about 2:1. This probably reflects our target population rather than a true difference in the incidence of adenomas. However, men are significantly more likely to develop colorectal cancer than women.15 Unfortunately, most reported case series of adenomas have studied populations heavily biased with men. Larger studies examining the influence of sex on adenoma frequency and distribution within the colon and rectum are needed. Well-designed overseas studies have confirmed that programs based on annual FOBT followed by colonoscopy for those with positive FOBT results significantly reduce anticipated mortality from colorectal cancer.16,17 Adding flexible sigmoidoscopy to FOBT to detect proximal adenomas seems sensible but adds significantly to cost. Indeed, a recent Australian economic study using computer modelling clearly showed that only FOBT or five- or 10-yearly colonoscopy are cost-effective bowel-cancer screening methods; flexible sigmoidoscopy alone or in combination with FOBT was not cost-effective.18 The distribution of adenomas found in our study adds weight to the recent suggestion that it is time to consider adding full colonoscopy to the menu of options available to general practitioners when discussing bowel cancer screening and prevention with their patients.19 References Coates M, Day P, McCredie M. Cancer in New South Wales: incidence and mortality 1992. Sydney: NSW Cancer Council, 1995. Australian Institute of Health and Welfare and the Australasian Association of Cancer Registries. Cancer in Australia 1991-1994 (with projections to 1999). Canberra: AIHW, 1998. Muto T, Bussey H, Morson B. The evolution of cancer in the colon and rectum. Cancer 1975; 36: 2251-2270. Winawer S. The National Polyp Study. Design, methods, and characteristics of patients with newly diagnosed polyps. The National Polyp Study Workgroup. Cancer 1992; 70: 1236-1245. National Health and Medical Research Council. Clinical practice guidelines. The prevention, early detection and management of colorectal cancer. Canberra: NHMRC, 1999. Australian Health Technology Advisory Committee. Colorectal cancer screening. Canberra: AGPS, 1997. Gut Foundation of Australia. Colorectal cancer prevention, diagnosis and treatment (public information booklet). Sydney: The Foundation, 1999. Winawer S, Fletcher R, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594-642. Kadakia S, Wrobleski C, Kadakia A. Prevalence of proximal colonic polyps in average-risk asymptomatic patients with negative fecal occult blood tests and flexible sigmoidoscopy. Gastrointest Endosc 1996; 44: 112-117. Shah S, Saunders B, Brooker J, Williams C. What happens during routine colonoscopy? An audit using magnetic positional imaging (MPI). Gut 1999; 44 Suppl 1: A105. Jacobs J, Burke C, Larive B. 60 cm flexible sigmoidoscopy, how far do we really get? [abstract] Gastroenterology 1999; 116 (4 Pt 2): A428. Collett J, Platell C, Fletcher D, et al. Distal colonic neoplasms predict proximal neoplasia in average-risk, asymptomatic subjects. J Gastroenterol Hepatol 1999; 14: 67-71. Rex D, Amitabh C, Vasudeva R. Prospective determination of distal colon findings in average-risk patients with proximal colon cancer. Gastrointest Endosc 1999; 49: 727-730. Basson M, Etter L, Panzini L. Rates of colonoscopic perforation in current practice. Gastroenterology 1998; 114: 1115. Rex D, Lehman G, Ulbright T, et al. Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender and family history. Am J Gastroenterol 1993; 88: 825-831. Mandel J, Bond J, Church T. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328: 1365-1371. Hardcastle J, Chamberlain J, Robinson M, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472-1477. Bolin T, Korman M, Stanton R. Positive cost effectiveness of early diagnosis of colorectal cancer. Colorectal Dis 1999; 1: 113-122. Bolin T, Korman M. How can we reduce the incidence and mortality of colorectal cancer? Med J Aust 1997; 166: 175-176. (Received 5 Nov 1999, accepted 24 Jan 2000) Authors' details Gastroenterology Unit and Department of Medicine, Monash Medical Centre, Melbourne, VIC. Fiona B Nicholson, FRACP, Fellow; Melvyn G Korman, PhD, FRACP, Director; Anthony I Stern, PhD, FRACP, Visiting Physician; Jack Hansky, FRACP, Visiting Physician. Reprints: Dr M G Korman, Department of Gastroenterology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168. m.kormanATshcn.com.au Make a comment Back to text

Fiona B Nicholson · Melvyn G Korman · Anthony I Stern · Jack Hansky

Editorial Preventing hepatitis C virus transmission in Australians who inject drugs Prevention, through harm minimisation, remains preferable to cure MJA 2000; 172: 55-56 Hepatitis C virus (HCV) infection is an uncontrolled epidemic in both the developed and the developing world. However, it is only in the developed world where average life expectancy is long enough to be influenced by the sequelae of HCV infection. The disease is very slowly progressive, and causes cirrhosis in approximately 15% of infected people over two or more decades; in approximately half of these, it then causes hepatic decompensation or hepatocellular carcinoma over another one or two decades.1Most people currently dying of HCV infection in Australia are middle-aged or elderly immigrants from Southern Europe, the Middle East and Asia. To date, 31.3% of liver transplants performed for hepatitis C infection in Australia2 and 52.4% of hepatocellular carcinomas diagnosed in people with HCV infection in Victoria3 have been in this group. These people have acquired the infection in their country of birth from cultural practices involving skin penetration, or medical interventions, including injections. Maintenance and expansion of the needle and syringe exchange programs will remain the single most important component of Australia's harm minimisation efforts However, current transmission of HCV infection in Australia is occurring largely within the culture of injecting drug use. Although the risk of transmission by an individual needlestick is not high (up to 6.1%4), the high prevalence of HCV infection among users, the frequency of injecting and the practices used have established a self-perpetuating system of transmission.5,6 Thus, it is likely that the future disease burden of hepatitis C-related illness in Australia will be carried largely by current or past injecting drug users. In this issue of the Journal, MacDonald et al examine the influence of harm reduction programs by measuring seroprevalence of HCV in people who attended a cross-section of needle and syringe exchange programs throughout Australia in 1995, 1996 and 1997.7 Their findings, which show that seroprevalence fell from 63% in 1995 to 50% in 1997, are encouraging. There may have been selection bias, but, if one assumes that this bias applies equally to all three years studied, there has been a 21% reduction in seroprevalence during that time. The results were even more striking in recent users, in whom there has been a 41% reduction. For some reason there was no additional reduction between 1996 and 1997. Does this mean the effect of harm reduction programs has plateaued? That there is a limit to their efficacy? That only a certain proportion of users can be influenced by education programs? While further studies are needed over the next two or three years to clarify this, these data strongly support the need for ongoing efforts at harm reduction and maintenance of needle and syringe exchange programs. Can we do more to reduce seroprevalence of HCV in people who inject drugs? There has been a great deal of debate in the public domain about the various prevention and treatment strategies for drug dependency. There is little to add, except to emphasise the need for continuing support services and harm-minimisation programs for those people who decide to embark on or continue with an injecting drug habit. Such support includes widespread availability of needle and syringe exchange programs and ready access to counselling and education facilities. Education includes strategies for primary and secondary prevention of injecting drug use, including diverting users to non-injecting routes of drug administration. Does antiviral treatment have anything to offer as a strategy to prevent transmission? The combination of interferon alfa and ribavirin has now become the benchmark for treatment of HCV infection, with a long term response rate of over 40% -- double that of interferon alfa monotherapy. As the marker of response (the polymerase chain reaction test for viral RNA) measures viraemia, it can be assumed that those who "respond" are not infectious. It is expected that the combination therapy will be licensed for treatment-na•ve patients in Australia in 2000. Currently, combination treatment is licensed under section 100 (s100) of the National Health Act 1953 (Cwlth) for people who have relapsed after interferon alfa monotherapy. With a response rate of over 40%, should we not be using this treatment in injecting drug users? The current s100 criteria for interferon alfa do not preclude treatment of current injecting drug users. However, there are three major potential problems which lead to caution in liver clinics. Firstly, there is the risk of reinfection: an injecting drug user needs to use scrupulous technique 100% of the time in order to avoid reinfection. Secondly, there is the risk of serious psychiatric effects with interferon alfa (psychotic reactions, cognitive impairment, severe depression including suicide attempts, and homicidal ideation),8 with suicides having occurred in Australia and overseas.9 Psychiatric reactions are more common in people with pre-existing psychological problems, chaotic lifestyles and those who lack social networks and supports. Interferon alfa can cause recidivism to injecting drugs, particularly in recent users, and this recidivism has been associated with major psychiatric problems.8 Unfortunately, funding for interferon in Australia has not been tied to any funding for counselling or psychiatric services. Thirdly, the other drug, ribavirin, is clearly teratogenic at low dose in all animal species studied, and can potentially cause embryotoxicity from either male or female parents.10 Additionally, ribavirin may be present in semen and cause teratogenicity in a woman already pregnant. It has a large volume of distribution and a long half-life (298 hours; see product information, available from Schering-Plough Pty Ltd, PO Box 231, Baulkham Hills, NSW 2153). Thus, people contemplating a course of ribavirin must be counselled about contraception -- both men and women must make sure no pregnancies occur during treatment and for six months afterwards, and additionally there should be no unprotected intercourse with a woman already pregnant. The product information for ribavirin advises two separate methods of contraception, one for the male and one for the female of a partnership. Clearly, at this stage, antiviral treatment cannot be safely advocated as a widespread public health method of reducing transmission of HCV in people who inject drugs. As a general rule it is safer to defer treatment until individuals have stopped injecting drugs for a long time, particularly as the rate of progression of HCV-related liver disease is so slow. While antiviral treatment may then be effective in clearing virus in those who have stopped injecting, it will have no effect on transmission, as these individuals are no longer part of the injecting population. The emphasis must therefore remain on concerted efforts to reduce the numbers of Australians who inject drugs, to provide support during this period in their lives, to reduce the number of times they actually inject, and to promote a safe, "self defence" injecting technique with every injection. Maintenance and expansion of needle and syringe exchange programs will remain the single most important component of Australia's harm-minimisation efforts. Adherence to the principles of harm minimisation is the only way to control this epidemic until a vaccine becomes available -- and this is unlikely to occur within a decade. Katrina J R Watson Deputy Director Department of Gastroenterology St Vincent's Hospital, Melbourne, VIC Seeff AB. Natural history of hepatitis C. Hepatology 1997; 26 (3 Suppl): 215-285. Zekry A, Whiting P, Crawford D, et al. Long term outcome of hepatitis C virus infection post liver transplantation. The Australian and New Zealand experience [abstract]. J Gastroenterol Hepatol 1999; 14: A171. Roberts SK, Sulaiman N, Giles G, et al. Rising incidence and risk factors for hepatocellular carcinoma in Victoria [abstract]. J Gastroenterol Hepatol 1999; 14: A194. Dore G, Kaldor J, McCaughan G. Systematic review of the role of polymerase chain reaction in defining infectiousness among people with hepatitis C virus. BMJ 1997; 315: 333-337. Crofts N, Thompson S, Kaldor J. Epidemiology of the hepatitis C virus. Communicable Diseases Intelligence Technical Report Series No. 3. Canberra: National Centre for Disease Control, Commonwealth Department of Health and Aged Care, and Communicable Disease Network Australia and New Zealand, May 1999. Australian National Council on AIDS and Related Diseases Hepatitis C Sub-Committee. Hepatitis C Virus Projections Working Group: estimates and projections of the hepatitis C virus epidemic in Australia. Sydney: National Centre in HIV Epidemiology and Clinical Research, University of NSW, August 1998. MacDonald MA, Wodak AD, Dolan KA, et al. Hepatitis C virus antibody prevalence among injecting drug users at selected needle and syringe programs in Australia, 1995-1997. Med J Aust 2000; 172: 57-61. Dusheiko G. Side effects of alpha interferon in chronic hepatitis C. Hepatology 1997; 26 (Suppl 1): 1125-1215. Hepatitis C National Data Base Project. Final report 1999. Newcastle: Hepatitis C National Data Base, 1999. Kochbar DM. Effects of exposure to high concentrations of ribavirin in devloping embryos. Pediatr Infect Dis J 1990; 9 (9 Suppl): S88-S90. Make a comment

Healthcare Accidental paracetamol overdosing and fulminant hepatic failure in children Fiona K Miles, Ramananda Kamath, Stuart F A Dorney, Kevin J Gaskin and Edward V O'Loughlin MJA 1999; 171: 472-475 See also Hynson Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Pathology Abstract Objective: To delineate clinical characteristics useful for identifying children with liver failure due to accidental paracetamol overdose. Design: Retrospective review of medical records of all patients admitted from 1985 to 1998 with fulminant hepatic failure. Setting: Royal Alexandra Hospital for Children, a tertiary referral centre for paediatric liver transplantation. Main outcome measures: Contribution of paracetamol to liver failure; other risk factors for liver failure; comparison of clinical features of paracetamol group and others. Results: 18 patients were identified. Eight were considered to have accidental paracetamol hepatotoxicity. In a further three, other risk factors were present but paracetamol was considered a major contributor to liver failure. The seven remaining patients had other risk factors for liver failure. Patients with paracetamol-induced liver failure usually had an acute prodromal illness with prolonged fasting and, at presentation, had encephalopathy, coagulopathy, very high transaminase levels, but disproportionately low total bilirubin levels. Five patients had hypoglycaemia. End-stage liver failure occurred in 4/11 of the paracetamol group compared with 7/7 of the others. Conclusion: Accidental paracetamol overdose is associated with fulminant hepatic failure in infants and children. Patients present with high transaminase levels and liver synthetic failure out of proportion to the level of serum bilirubin. Prompt identification of such patients is important as many recover with supportive therapy. Introduction Paracetamol is a commonly used antipyretic and analgesic medication; in 1996, it was the second most common drug used in Australia, with 4.75 million units dispensed.1 There is a large range in the preparations of doses available, and the potential for accidental overdose due to confusion over concentration and frequency of dosing is high.2Intentional paracetamol overdose is a well-recognised cause of fulminant liver failure.2 However, there are few reports of accidental overdose due to recurrent ingestion of high therapeutic doses in children.3-6 Alonso et al reported seven children with fulminant liver failure without obvious cause.5 All patients had ingested paracetamol, but serum paracetamol levels were not in the toxic range. The authors postulated that, although paracetamol may have contributed to the liver injury, it was not causative. Two other reports describe accidental multiple dosing causing liver failure in children, with many patients receiving doses in the recommended therapeutic range.3,6 Prodromal illness associated with prolonged fasting was also recognised as potentially important in the development of liver injury.4,5 Since 1985, the Royal Alexandra Hospital for Children has been a tertiary referral centre for paediatric liver transplantation. Over this period, 19 patients have presented with acute liver failure. Our aims were to review all cases of acute liver failure, to identify patients with accidental (overdose with therapeutic intent) paracetamol-induced liver failure, and to define clinical features which may be useful in identifying such cases. Methods All patients at the Royal Alexandra Hospital with fulminant hepatic failure -- severe acute liver injury with no pre-existing liver disease resulting in encephalopathy within eight weeks of onset -- are managed by members of the liver transplant service. We reviewed case records of such patients for a history of liver disease, presenting symptoms, pre-existing history of paracetamol ingestion, clinical status at presentation, laboratory investigations and outcome. Paracetamol hepatotoxicity was considered likely if patients with liver failure had: a history of paracetamol ingestion over several days, confirmed by the finding of paracetamol in the blood; and exclusion (by routine laboratory testing) of other known causes of acute liver failure, such as viral hepatitis (A, B, C, Epstein-Barr virus, cyto-megalovirus, HSV-6, varicella or adenovirus), drug- or toxin-induced hepatotoxicity, inborn errors of metabolism (Wilson's disease, α1-antitrypsin deficiency, and fatty acid oxidation abnormalities). Approval for our study was obtained from the hospital's institutional ethics committee. Results Ninteen patients were identified, aged 6-165 months. One adolescent developed liver failure from suicidal overdose (30 g), and made a complete recovery with conservative treatment; this patient was excluded from the study. Paracetamol hepatotoxicity Eleven of the remaining 18 patients had presumed paracetamol hepatotoxicity. The patient data shown in the Table represent peak levels of study parameters or stage of encephalopathy. All patients had coagulopathy, elevated transaminase levels, and abnormal total serum bilirubin. Eight patients (numbers 1-8, Table) were identified as having paracetamol overdose as the only risk factor for liver failure. All eight patients had a history of a prodromal illness for which they received paracetamol for 4-21 days prior to the identification of liver disease. Reported paracetamol intakes ranged from 20 to 200 mg/kg per day. Paracetamol was detected in the blood of all eight patients, and all were encephalopathic (stage I-III) at presentation. Patients 1, 2, 3, 5 and 7 were hypoglycaemic (blood glucose levels < 3 mmol/L) at admission. Liver failure resolved with supportive treatment in six of these patients; Patients 2 and 6 died while awaiting liver transplants. Patient 5 survived, but had severe neurological sequelae as a result of protracted hypoglycaemia and stage IV encephalopathy. Patient 4 was admitted to the intensive care unit, but was not initially recognised as having liver failure. Patients 9, 10 and 11 had probable paracetamol hepatotoxicity, but also had other risk factors for liver injury. Patient 9 had Ewing's sarcoma and had been receiving chemotherapy. Multiple doses of paracetamol had been administered in hospital before the onset of liver failure. At postmortem, hepatic centrilobular necrosis consistent with paracetamol hepatotoxicity was found. Patient 10 also had a history of paracetamol ingestion, although the quantity could not be determined from the history. However, a high level of paracetamol was detected in the blood. The patient had had one previous admission with mumps encephalitis, which resulted in epilepsy and mental retardation. He had also been taking sodium valproate for seizures for several years, with no evidence of liver abnormalities. The patient died of end-stage liver failure and post-mortem revealed severe centrilobular necrosis consistent with paracetamol- rather than valproate-induced liver injury. Patient 11 had a mild prodromal illness due to Epstein-Barr virus infection, but ingested large quantities of paracetamol and presented with the clinical picture as described for Patients 1-8. Coagulopathy precluded liver biopsy in this group of patients. Metabolic studies: Urinary metabolic studies failed to reveal abnormal metabolites indicative of fatty acid oxidation defects in Patients 1, 2, 5, 6, 7 and 8, and skin fibroblast assays for fatty acid oxidation defects were normal in Patients 3, 6, 7 and 8. For Patient 4, no metabolic studies were performed. Other causes of liver failure Seven patients presented with fulminating liver failure from other causes, including Wilson's disease (1), cytomegalovirus infection (1), hepatitis B virus infection (1), presumed viral hepatitis (3), and an adverse reaction to dapsone (1). All patients presented with evidence of severe synthetic failure (coagulopathy and hypoalbuminaemia) and hepatic encephalopathy. Distinguishing paracetamol hepatotoxicity The Figure compares the serum bilirubin levels plotted against alanine transaminase levels in both groups of patients. In contrast to patients with other causes of acute liver failure, patients with presumed paracetamol hepatotoxicity all had serum bilirubin levels less than 200 µmol/L, and most had alanine transaminase levels greater than 4000 IU/L. Hypoglycaemia was not detected in any of the patients with liver failure from causes other than paracetamol, and all patients in this group either died or received transplants. Discussion Clinical features Accidental paracetamol overdose was the likely cause of acute liver failure in most children in this series presenting to a single paediatric institution. Eight of the 18 patients had likely paracetamol-induced liver failure due to accidental overdose, and in a further three paracetamol was a major risk factor. A distinct clinical pattern emerges when the patients with definite or presumed paracetamol toxicity are compared with patients with other causes of fulminant hepatic failure. Patients with paracetamol toxicity presented with a non-specific prodromal illness, often with fasting and/or vomiting. At the time of hospitalisation they had evidence of severe synthetic failure, often with associated hypoglycaemia, coagulopathy and mild encephalopathy, but with disproportionately low bilirubin levels. Moreover, most patients recovered with supportive therapy. A history of paracetamol ingestion over several days is important in establishing the diagnosis of paracetamol toxicity. In our study, reported ingestion of as little as 20 mg/kg per day over a protracted period was associated with liver failure. Similar toxic dosage ranges have been reported in other studies of children,3,5 raising the question of whether some susceptible children could suffer acute liver failure as a result of therapeutic doses of paracetamol ingested over several days. However, it is important to emphasise that the paracetamol intake data reported in this study, as in previous published reports, rely on history alone. The dosages reported by parents could not be verified by other means. Whether therapeutic doses of paracetamol could result in liver failure in susceptible children remains unresolved owing to the poor quality of the existing paediatric data. Serum paracetamol levels Paracetamol was detected in the serum of patients with presumed paracetamol hepatotoxicity. Although other investigators have used a level of 0.04 mmol/L3,4 as indicative of toxicity, it is not clear that this is a meaningful level in an individual with repeated ingestions over several days. A level of 40 µmol/L or greater at 24 hours after the ingested dose is thought to predict the likely development of liver failure, as portrayed in the nomogram adapted by Rumack and Matthews.7 However, this nomogram was derived from adult patients presenting with liver failure from a single suicidal overdose. No studies have addressed the question of serum levels likely to predict hepatic failure after repeated doses. We observed that the possible role of paracetamol was, on occasion, discounted because paracetamol levels were lower than those predictive of the development of liver failure from the nomogram. Poor correlation between paracetamol levels and liver toxicity with accidental overdose has been observed in a large series of adult patients in whom less than 50% had peak serum levels greater than 10 µg/mL (40 µmol/L).4 Similarly, low levels were reported in a small series of children.5 Nevertheless, serum paracetamol levels should be measured routinely in the investigation of children presenting with acute liver failure as soon as possible after assessment, but should be interpreted with caution. A recent study of paracetamol toxicity in adults by Schiodt et al identified a distinct group of patients who developed liver dysfunction after accidental poisoning with therapeutic intent.4 This group of 21 patients had ingested frequent doses of paracetamol for pain relief. Toxicity may have been compounded by prior starvation.2 Mortality in that study (4/21) was similar to ours, but was substantially higher than in a group of adult patients with non-accidental overdose. Some doubts about the role of paracetamol in causing fulminant hepatic failure in the study by Schiodt et al have been raised, as a high proportion of patients had a history of concurrent alcohol abuse and dosage levels were considered by some to be too low to cause toxicity.8-11 In contrast to that study of adults, studies in children raise considerable concern that accidental paracetamol overdose causes liver failure in this age group.3,5 However, it is important to note that all the reported series in children (including our own) are anecdotal reports. No studies have included a control group or undertaken a case-control study design, although liver biopsies were performed in six of seven patients in one series.5 While one could argue that the association between accidental overdose and liver failure in children is speculative, several arguments support the likely association with paracetamol: Suicidal overdose in adults produces acute liver failure with a clinical and biochemical picture very similar to that reported in our study of overdose due to repeated ingestion. The presence of severe liver synthetic failure and encephalopathy with the pattern of liver function tests we describe (see Figure) is a very atypical presentation for most diseases which produce liver failure in children. In our study, four children had centrilobular necrosis on postmortem examination, a finding consistent with paracetamol hepatotoxicity. While some of the clinical characterisics, such as prodromal illness, hypoglycaemia, high transaminase levels and coagulopathy, would be consistent with Reye's syndrome,12 it is not likely that this diagnosis would explain the abnormalities which we attribute to paracetamol toxicity. Recent in-vitro and animal studies indicate that paracetamol or its metabolites impair mitochondrial metabolism, and this effect occurs before hepatocyte necrosis.13-15 In this regard, paracetamol hepatotoxicity demonstrates some remarkable clinical and biochemical similarities to some inborn errors of fatty acid oxidation which can present with fulminant liver failure.16 Despite several attempts to define a safe therapeutic regimen, there is still no consensus as to the appropriate dose, or even efficacy, in children. One report recommended single doses of 10-15 mg/kg four-hourly as a "safe maximum".17 However, Nahata et al demonstrated that paracetamol may accumulate substantially, with raised concentrations after therapeutic doses for two to three days, even with doses of 13 mg/kg 24-hourly.18 One study which did review the potential for chronic overdose in children was done by Penna et al,19 in which 190 of 299 paediatric inpatients received paracetamol for indications of fever and postoperative pain. Most were prescribed four-hourly doses, with potential for greater than 90 mg/kg per day. Nearly a quarter of the high doses were for children under 12 months of age. Although it can be argued that paracetamol "is commonly administered to children . . . for most febrile illnesses",5 and thus can be a frequent coincidental association, there is evidence that accidental overdose while ingesting high therapeutic doses of paracetamol for pain and fever relief may cause fulminating liver failure in children. Clinicians should be alerted to the possibility of paracetamol toxicity in an infant or child presenting with a prodromal illness associated with fasting and the regular ingestion of paracetamol over several days. Hypoglycaemia, severe synthetic failure and encephalopathy with very high transaminase levels (above 4000 IU/L) and a serum bilirubin level less than 200 µmol/L would support the diagnosis. It is important to distinguish this group of patients, as the prognosis for recovery is good with conservative therapy. If N-acetylcysteine is instituted early, liver transplantation may be avoided. References Commonwealth Department of Health and Family Services. Top 10 drugs. Australian Prescriber 1997; 20: 92. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995; 346: 547-552. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22-27. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337: 1112-1117. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127: 888-894. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300-304. Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871-876. Walker AM. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 543. Avorn J. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 543-544. Rao RB, Hoffman RS. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 544. Makin AJ, Williams R, Bernal W. Acetaminophen toxicity in an urban county hospital [letter]. N Engl J Med 1998; 338: 544. Diagnosis and treatment of Reye's syndrome. JAMA 1981; 246: 2441-2444. Burcham PC, Harman AW. Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J Biol Chem 1991; 266: 5059-5054. Vendemiale G, Grattagliano I, Altomare E, et al. Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat. Biochem Pharmacol 1996; 52: 1147-1154. Nazareth WM, Sethi JK, McLean AE. Effect of paracetamol on mitochondrial membrane function in rat liver slices. Biochem Pharmacol 1991; 42: 931-936. Tyni T, Palotie A, Viinikka L, et al. Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients. J Pediatr 1997; 130: 67-76. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol 1983; 3: 321-327. Nahata MC, Powell DA, Durrell DE, Miller MA. Acetaminophen accumulation in pediatric patients after repeated therapeutic doses. Eur J Clin Pharmacol 1984; 27: 57-59. Penna AC, Dawson KP, Penna CM. Is prescribing paracetamol "pro re nata" acceptable? J Paediatr Child Health 1993; 29: 104-106. (Received 25 Jun, accepted 2 Sep, 1999) Authors' details The Royal Alexandra Hospital for Children, Sydney, NSW. Fiona K Miles, MB ChB, Fellow in Intensive Care; Ramananda Kamath, MD, FRACP, Associate Professor and Staff Specialist, Department of Gastroenterology; Stuart F A Dorney, MB BS, FRACP, Staff Specialist, Department of Gastroenterology; Kevin J Gaskin, MD, FRACP, Professor and Staff Specialist, Department of Gastroenterology; Edward V O'Loughlin, MD, FRACP, Staff Specialist, Department of Gastroenterology. Reprints: Dr E V O'Loughlin, Department of Gastroenterology, The Royal Alexandra Hospital for Children, PO Box 3515, Parramatta, NSW 2124. tedoATnch.edu.au Clinical characteristics of 11 patients with liver failure due to paracetamolPatient: 1Age (months): 21Paracetamol dosage (mg/kg per day): 20 (21 days) & 171 (last day)Serum:Paracetamol level (µmol/L): 10 (D2)*Bilirubin level (µmol/L): 123Alanine transaminase level (IU/L): 9618PT INR: 3.3Hepatic coma stage: IIOutcome: ResolvedPatient: 2Age (months): 63Paracetamol dosage (mg/kg per day): 100 (6 days)Serum:Paracetamol level (µmol/L): 560 (D1)*Bilirubin level (µmol/L): 87Alanine transaminase level (IU/L): > 10 000PT INR: 9.7Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 3Age (months): 36Paracetamol dosage (mg/kg per day): Very frequent oral and rectal dosesSerum:Paracetamol level (µmol/L): 30 (D2)*Bilirubin level (µmol/L): 70Alanine transaminase level (IU/L): > 10 000PT INR: 4Hepatic coma stage: IIOutcome: ResolvedPatient: 4Age (months): 77Paracetamol dosage (mg/kg per day): 200 (11 days)Serum:Paracetamol level (µmol/L): 30 (D6)*Bilirubin level (µmol/L): 19Alanine transaminase level (IU/L): 1216PT INR: 1.4†Hepatic coma stage: IIIOutcome: ResolvedPatient: 5Age (months): 31Paracetamol dosage (mg/kg per day): 71 (4 days)Serum:Paracetamol level (µmol/L): 160 (D1)*Bilirubin level (µmol/L): 143Alanine transaminase level (IU/L): > 10 000PT INR: > 20Hepatic coma stage: IVOutcome: Resolved, severe brain damagePatient: 6Age (months): 129Paracetamol dosage (mg/kg per day): 20 (7 days)Serum:Paracetamol level (µmol/L): 180 (D1)*Bilirubin level (µmol/L): 82Alanine transaminase level (IU/L): > 10 000PT INR: 5Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 7Age (months): 6Paracetamol dosage (mg/kg per day): UnknownSerum:Paracetamol level (µmol/L): 160 (D1)*Bilirubin level (µmol/L): 94Alanine transaminase level (IU/L): 9 170PT INR: 6.9Hepatic coma stage: IIIOutcome: ResolvedPatient: 8Age (months): 54Paracetamol dosage (mg/kg per day): 74mg/kg/day (5 days) & 150mg/kg/day (final day)Serum:Paracetamol level (µmol/L): 900 (D1)*Bilirubin level (µmol/L): 57Alanine transaminase level (IU/L): 8 300PT INR: 5.4Hepatic coma stage: IIOutcome: ResolvedPatient: 9Age (months): 79Paracetamol dosage (mg/kg per day): Unknown (frequent dosing over several days)Serum:Paracetamol level (µmol/L): 70 (D1)*Bilirubin level (µmol/L): 185Alanine transaminase level (IU/L): 4 300PT INR: 3.1Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 10Age (months): 132Paracetamol dosage (mg/kg per day): UnknownSerum:Paracetamol level (µmol/L): 180 (D1)*Bilirubin level (µmol/L): 195Alanine transaminase level (IU/L): 3 620PT INR: 4.2Hepatic coma stage: IVOutcome: Died (PM: centrilobular necrosis)Patient: 11Age (months): 106Paracetamol dosage (mg/kg per day): 175 (7 days)Serum:Paracetamol level (µmol/L): 80 (D3)*Bilirubin level (µmol/L): 102Alanine transaminase level (IU/L): 6 700PT INR: 2.4Hepatic coma stage: IIIOutcome: Resolved* Days post admission to hospital. †Alanine transaminase level and INR measured on admission to hospital but not subsequently, despite deterioration of coma stage. PM = postmortem. OD = overdose. PT-INR = international normalised ratio (of prothrombin time). Normal ranges: serum bilirubin, 1-15 µmol/L; alanine transaminase, 10-50 IU/L; INR, 1-1.2. Back to textBack to text

Fiona K Miles · Ramananda Kamath · Kevin J Gaskin · Edward V O'Loughlin

Lessons from Practice Childhood hepatotoxicity with paracetamol doses less than 150 mg/kg per day MJA 1999; 171: 497 Paracetamol is widely used as an antipyretic and analgesic. Adverse effects are regarded as unlikely at doses below 150 mg/kg per day.1 However, lower doses have resulted in hepatotoxicity,2 and there is growing evidence of the potential for hepatotoxicity in children given multiple therapeutic or supratherapeutic doses of paracetamol.3-6The nomogram devised by Rumack and Matthews7 was based on data obtained from previously well adult patients who had taken a single large dose of paracetamol. The relevance of this to children given multiple doses in the context of a febrile illness is unknown, particularly as the metabolism in this population appears to be quite different.8 It has been suggested that the therapeutic index for paracetamol may be as low as 1.7,9 and that sick children under the age of two years given in excess of 90 mg/kg per day for more than one day should be regarded as being at higher risk.6 The product information recommends a maximum daily dose of 60 mg/kg, but it is not uncommon for children to receive doses in excess of 90 mg/kg per day in the hospital setting.10 Although the number of reported cases of hepatotoxicity induced by therapeutic doses of paracetamol is small, it is possible that cases have gone unrecognised. It is important to administer the drug with caution and according to current dosage guidelines. Case reports Case 1: Six days before transfer to our hospital, a previously well four-year-old, 20 kg girl had commenced a course of cefaclor for otitis media, and over 72 hours she received about 2400 mg of paracetamol in divided doses. She was admitted to her local hospital with fever (39ºC), abdominal pain, vomiting and diarrhoea. Her aspartate transaminase (AST) level was 2050 U/L (normal range, < 45 U/L). She was tachypnoeic and hypoxic, and over the next 17 hours received 2800 mg (140 mg/kg) paracetamol. Her condition deteriorated. Results of liver function tests were: AST, 4580 U/L (Figure A); alanine transaminase, 2785 U/L (normal range, < 55 U/L); and serum bilirubin, 27 µmol/L (normal range, < 15 µmol/L). The international normalised ratio of prothrombin time was 4.2, and activated partial thromboplastin time, 47 s (control, < 42 s). Left lower lobe pneumonia was diagnosed, and treatment commenced with fresh frozen plasma, vitamin K, and antibiotics. The AST level rose to 11 475 U/L. The paracetamol level 22 hours after the last documented dose of the drug was 55 µmol/L. N-acetylcysteine (150 mg/kg) was administered intravenously. After the child was transferred to our hospital, intravenous N-acetylcysteine was continued (10 mg/kg/h for 32 h). Abdominal ultrasound revealed a large homogeneous liver and a small amount of ascites. Serology for hepatitis A and B, Epstein-Barr virus, cytomegalovirus and Mycoplasma pneumoniae was negative. Respiratory syncytial virus was detected in a nasopharyngeal aspirate. Blood cultures were negative. Stool examination revealed no viral agent. The patient was discharged after seven days, with an AST level of 171 U/L. Three months later she was completely well, with normal liver function tests. Case 2: A 12-year-old, 43 kg boy with Duchenne's muscular dystrophy was admitted for posterior spinal fusion and tendon-release surgery. He was anaesthetised using propofol and nitrous oxide, and during the operation required transfusion for a one-litre blood loss. He returned to the ward on a morphine infusion (20 µg/kg/h) and cephazolin (1 g eight-hourly). Over the next 24 hours he received a total dose of 3000 mg (70 mg/kg) paracetamol rectally. Similar total doses were given over the next five days, with a maximum of 4650 mg (108 mg/kg) in any 24-hour period. Liver function tests taken the day after surgery revealed an AST level of 193 U/L (Figure B) and a gamma-glutamyl transpeptidase (GGT) level of 43 U/L (normal range, < 40 U/L). He developed paralytic ileus 48 hours after surgery; this resolved with intravenous hydration. On day seven, he became irritable and disoriented and was pale, icteric and lethargic. Results of investigations were: serum bilirubin, 120 µmol/L; GGT, 68 U/L; AST, 7377 U/L; and ammonia, 88 µmol/L (normal range, < 50 µmol/L). His serum paracetamol level was 528 µmol/L. The haemoglobin level was 68 g/L and he received two units of packed cells. Serology for hepatitis B and C was negative. The paracetamol level was 206 µmol/L 34 hours after the last dose, but, as the liver enzyme levels were falling and the child's conscious state improving, N-acetylcysteine was not administered. He was discharged 22 days after surgery with an AST level of 113 U/L. Back to text Jenny L Hynson,* Mike South** * Consultant Paediatrician ** Associate Professor, and Director Department of General Paediatrics, Royal Children's Hospital Flemington Road, Parkville, VIC 3052 Rumack BH. Acetaminophen overdose in young children. Am J Dis Child 1984; 138: 428-433. Schoidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337: 1112-1117. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr 1998; 132: 22-27. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127: 888-894. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300-304. Kearns GL, Leeder JS, Wasserman GS. Acetaminophen overdose with therapeutic intent [editorial]. J Pediatr 1998; 132: 5-8. Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871-876. Penna A, Buchanan N. Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol 1991; 32: 143-149. Heubi JE, Bien JP. Acetaminophen use in children: more is not better [editorial]. J Pediatr 1997; 130: 175-177. Penna AC, Dawson KP, Penna CM. Is prescribing paracetamol "pro re nata" acceptable? J Paediatr Child Health 1993; 29: 104-106.

Healthcare Hepatitis C: an economic evaluation of extended treatment with interferon Alan Shiell, Sue Brown and Geoff C Farrell MJA 1999; 171: 189-193 Abstract - Introduction - Methods - Results - Discussion - References - Authors' details Abstract Objectives: To re-evaluate the cost effectiveness of treating hepatitis C virus (HCV) infection with interferon alfa (IFα) in Australia, taking into account changes in clinical practice. Design: A decision-analytic method (Markov model) was used to simulate the costs and effects of 6 months and 12 months of treatment with IFα versus no treatment (conventional management). Both costs and effects were modelled over 30 years. Data sources: Published meta-analysis of the effectiveness of treatment, professional judgement about treatment protocols, scheduled medical fees, diagnosis-related costs for hospital admission, and a literature search for quality-of-life weights. Patients: A hypothetical cohort of 1000 patients with chronic HCV infection aged 40 years at the start of treatment. Main outcome measures: Incremental costs per life-year gained and per quality-adjusted life-year (QALY) gained. Results: Compared with no treatment, IFα treatment for 6 months results in an extra 94.2 life-years or 320.1 QALYs at an extra cost of $1.8 million (after discounting at 3%) in a cohort of 1000 patients. Discounted cost per life-year gained is $19 110, which is about a quarter of the cost reported in 1994. The discounted cost per QALY gained is $5625. Extended treatment for another 6 months results in an additional 89.0 life-years saved or 170.8 QALYs gained at an incremental discounted cost of $15 835 per life-year gained and $8250 per QALY gained. Conclusions: The cost effectiveness of IFα treatment for HCV infection has improved as a result of better patient selection, cost reductions and enhanced effectiveness of extended treatment. The results are sensitive to assumptions made about quality of life and the discount rate. Introduction Infection with the hepatitis C virus (HCV) is an important public health problem in Australia. It is estimated that there are at least 100 000 people carrying the virus and that up to 10 000 new cases are diagnosed each year.1 As many as 85% of those with acute HCV infection will develop chronic infection, and, of these, a significant proportion will develop cirrhosis and hepatocellular carcinoma (HCC). The only approved treatment for chronic HCV infection, interferon alfa (IFα), is expensive, has significant adverse effects and is effective in only 10%-35% of patients. The cost effectiveness of treatment is uncertain. Decision-analytic techniques have been used to simulate the expected costs and effects of treatment, and several economic evaluations of IFα have been published.2-7 The only Australian study (published in 1994)3 estimated the cost per life-year gained by treatment with IFα to be $33 000 in patients with cirrhosis at the start of treatment and $71 000 for patients without cirrhosis. These figures are substantially higher than those reported elsewhere, reflecting a more cautious view of the long term effectiveness of IFα and the exclusion of the broader benefits of therapy, such as its assumed effects on employment and production capacity. The impact that IFα has on the natural history of HCV infection is now better known. Treatment is discontinued in patients who fail to show a response after 12 weeks, with no reduction in effectiveness but with substantial cost savings. Further, several studies have shown benefits of extended treatment over 12 months rather than 6 months, and this has become the recommended treatment period in most countries including Australia. The effect that this has on cost effectiveness is not clear, as both costs and benefits are likely to increase. Our aim is to update our previous estimate of the cost effectiveness of IFα in the treatment of chronic HCV infection.3 Under section 100 of the Health Act 1953 (Cwlth) (Highly Specialised Drugs Program), subsidised treatment is restricted to patients with no signs of cirrhosis at start of treatment and we have restricted our analysis to such patients. Methods The costs and effects of IFα treatment were simulated by a decision-analytic method (the Markov model) in a hypothetical cohort of 1000 patients with chronic HCV infection aged 40 years at start of treatment (the mean age at diagnosis is 42 years). Both costs and effects were modelled over 30 years. The cost effectiveness of treatment with IFα over 6 months versus no treatment (ie, conventional management only) was re-evaluated, incorporating changes in clinical practice, treatment costs and the price of IFα. The incremental costs and effects of moving from 6 months to 12 months' treatment were then estimated. The software used was Microsoft Excel 97. The assumptions and methods for the decision analytic technique are shown in the Box. Results The net cost of 6 months' treatment with IFα for chronic HCV infection (ie, the cost of treatment minus the cost of conventional management of the disease) was estimated to be $1800 per patient after discounting at 3%. Treatment with IFα results in an extra 94.2 discounted life-years saved or 320.1 additional (discounted) QALYs (Table 2). The incremental cost per life-year saved was $19 110, which is about a quarter of the cost reported in our previous study.3 The incremental cost per QALY gained was $5625. Extending treatment from 6 to 12 months results in an additional 89.0 discounted life-years gained or 170.8 discounted QALYs at incremental costs of $15 835 per life-year gained and $8250 per QALY gained. Average cost per unit of outcome increases as the duration of the model is reduced. As duration of the model acts as a proxy for age at the start of treatment, this finding suggests that treatment is less cost effective in older age groups. The sensitivity analysis (Table 3) suggests that the results for 6 months' treatment are robust with respect to assumptions made about rates of disease progression, the long term effectiveness of IFα, the price of IFα and the exclusion of patients not responding after 12 weeks. The most important variables are the choice of discount rate and the adjustment for quality of life (Table 3). Relatively minor adjustments to the quality-of-life weight for treatment have a large effect on cost per QALY gained. In the extreme, the adverse effects of treatment offset any gains in quality of life brought about by disease resolution. The effect of 12 months' treatment over 6 months' treatment is also sensitive to changes in the discount rate and the duration of the model and, in addition, is more sensitive to assumptions made about disease progression and treatment effectiveness. Discussion Our results suggest that the cost per life-year gained from 6 months' treatment with IFα is lower than when it was first evaluated in an Australian context in 1994.3 This change is attributable to three main factors: a reduction in the cost of treating people with IFα; a reduction in the price of IFα itself; and cessation of treatment at 12 weeks in those who fail to show a reduction in serum alanine aminotransferase levels. The latter has been clinical policy in Australia since IFα was first listed for public subsidy in 1994, but our initial evaluation preceded this.3Quality adjustment of the outcomes also has a substantial effect on the cost-effectiveness ratios, suggesting that the major impact of IFα treatment is on improving quality of life rather than increasing life expectancy through the prevention of cirrhosis. There is also the relief offered to those in whom the infection is resolved. However, the sensitivity of the results to changing assumptions about the effect of the disease and its treatment on quality of life reinforces the need for further research into the subjective impact of HCV infection. Only one other study has considered the cost effectiveness of 12 months' versus 6 months' therapy.7 Consistent with our results, it concluded that treatment over 12 months may be cost effective, except in patients older than 60 years of age. The cost-effectiveness ratios reported here compare favourably with many other public health interventions, such as screening for breast and cervical cancer.20,21 However, there are problems in comparing the results of economic evaluations, particularly when different methods have been used.22 Furthermore, if the benefits of extended treatment with IFα are to be realised within a limited healthcare budget, then some other program or activity must be dropped or reduced in scale to accommodate the increase in expenditure. Thus, before drawing conclusions about cost effectiveness, one should compare the benefits of IFα treatment with the benefits of the other program or activity affected.23 See Box for summary points. Caution is especially warranted when, as in this case, a decision-analytic model has been employed, as it is often difficult to assess the validity of the assumptions made. The protracted nature of HCV infection, however, makes it difficult to assess the cost effectiveness of treatment by another means.24,25 Decisions on when and how to use IFα have to be made with available data. However, our comprehensive sensitivity analysis showed that, for most of the assumptions made, the results appear to be robust. The exceptions are the two subjective variables -- the utility attached to different disease endpoints and the rate at which future costs and benefits are discounted. HCV infection is not the benign disease it was once believed to be, but little is known about the impact it has on people's lives or the lengths to which they might go for relief. Our results are particularly sensitive to assumptions made about the relative effect of living with chronic infection, and its associated risks of long term sequelae versus the known risks and the uncertain effectiveness of treatment. Individual attitudes to risk and time preference will affect the perceived cost effectiveness of treatment. Further research is needed to examine the personal and social impact of HCV infection and the utility of its treatment.26 References Australian Health Ministers' Advisory Council. National Hepatitis C Action Plan, October 1994. Canberra; AGPS, 1994. 2. Garcia de Ancos JL, Roberts JA, Dusheiko GM. An economic evaluation of the costs of a-interferon treatment for chronic active hepatitis due to hepatitis B or C virus. J Hepatol 1990; 11: S11-S18. Shiell A, Briggs A, Farrell G. The cost-effectiveness of alpha interferon in the treatment of chronic active hepatitis C. Med J Aust 1994; 160: 268-272. Dusheiko GM, Roberts JA. Treatment of chronic type B and C hepatitis with interferon alfa: an economic appraisal. Hepatology 1995; 22: 1863-1873. Joliet E, Vanlemmens C, Kerleau M, et al. Cost-effectiveness analysis of the treatment of chronic hepatitis C. Gastroenterol Clin Biol 1997; 21: 336-338. Bennet WG, Inoue Y, Beck R, et al. Estimates of the cost-effectiveness of a single course of interferon-a 2b in patients with histologically mild hepatitis C. Ann Intern Med 1997; 127: 855-865. Kim WR, Poterucha JJ, Hermans JE, et al. Cost-effectiveness of 6 and 12 months of interferon-a therapy for chronic hepatitis C. Ann Intern Med 1997; 127: 866-874. National Institutes of Health Consensus Development Panel statement: management of hepatitis C. Hepatology 1997; 26(3 Suppl 1): 2S-10S. Fattovitch G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112: 463-472. Australian Bureau of Statistics. Deaths: Australia 1994. Canberra: ABS, 1994. (Catalogue No. 3302.0.) Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24: 778-789. Carithers RL Jr, Sugano D, Bayliss M. Health assessment for chronic HCV infection: results of quality of life. Dig Dis Sci 1996; 41: 75S-80S. Davis GL, Balart LA, Schiff ER, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther 1994; 16: 334-343. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998; 27: 209-212. National Health and Medical Research Council. A strategy for the detection and management of hepatitis C in Australia. Canberra: NHMRC/AGPS, 1997. Commonwealth Department of Health and Family Services. Medical Benefits Schedule. Nov 1996. Canberra; AGPS, 1996. Commonwealth Department of Health, Housing, Local Government and Community Services. Manual of Resource Items and their Associated Costs. Canberra: AGPS, November 1993. Drummond MF, Brandt A, Luce B, Rovira J. Standardising methodologies for economic evaluation in health care. Int J Technol Assess Health Care 1993; 9: 26-36. Gold MR, Siegel JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York: Oxford University Press, 1996: 230. AHMAC Breast Cancer Screening Evaluation Committee. Breast screening in Australia: future directions. Canberra: Australian Institute of Health and Welfare, 1990. AHMAC Cervical Cancer Screening Evaluation Committee. Cervical Screening in Australia: options for change. Canberra: Australian Institute of Health and Welfare, 1991. Salkeld G, Davey PD, Arnolda G. A critical review of health-related economic evaluations in Australia: implications for health policy. Health Policy 1995; 31: 111-125. Birch S, Donaldson C. Cost-benefit analysis: dealing with the problems of indivisible projects and fixed budgets. Health Policy 1987; 7: 61-72. Bennet WG, Pauker SG, Davis GL, Wong JB. Modeling therapeutic benefit in the midst of uncertainty: therapy for hepatitis C. Dig Dis Sci 1996; 41: 56S-62S. Koff RS, Seeff LB. Economic modeling of treatment of chronic hepatitis B and chronic hepatitis C: promises and limitations. Hepatology 1995; 22: 1880-1885. Owens DK. In the eye of the beholder: assessment of health-related quality of life. Hepatology 1998; 27: 292-293. (Received 20 Nov 1998, accepted 3 May 1999) Authors' details Social and Public Health Economics Research Group (SPHERe), Department of Public Health and Community Medicine, University of Sydney, Sydney, NSW. Alan Shiell, MSc(Econ), Honorary Research Associate. Medical Benefits Fund of Australia, Sydney, NSW. Sue Brown, MPH, BPharm, Pharmacy Manager, Provider Relations. Department of Medicine, Westmead Hospital, University of Sydney, NSW. Geoff C Farrell, MD, FRACP, Storr Professor of Medicine. Reprints will not be available from the authors. Correspondence: Mr A Shiell, Social and Public Health Economics Research Group (SPHERe), Department of Public Health and Community Medicine, University of Sydney (A27), NSW 2006. Email: alansATpub.health.usyd.edu.au Assumptions and methods for the decision analytic technique Natural history of hepatitis C (HCV) Chronic HCV infection to cirrhosis: The rate of progression was assumed to be 20% at 20 years,8 consistent with experience in patients attending liver clinics, but is higher than in a community sample. Cirrhosis to hepatocellular carcinoma (HCC): Rates of progression range from 1% to 4% per year and are higher in older age groups.8 We have assumed an annual rate of 1.4% (14% over 10 years), which is the lowest rate from more than 10 published studies from Europe and Japan.9 The small chance of HCC developing in patients without cirrhosis (< 0.25% per year)8 was ignored. Cirrhosis to advanced liver failure: We assumed that 20% of the cohort would progress to advanced liver failure over 10 years from the onset of cirrhosis.8 Death: All patients developing HCC or advanced liver failure were assumed to die within 2 years of diagnosis. Deaths from other causes were estimated from Australian life tables.10 Effectiveness of IFα treatment Previous evaluation: In our previous evaluation,3 we assumed that 6 months' treatment with IFα would be effective in 20% of cases overall and 26% of cases without cirrhosis at the start of treatment. A recent meta-analysis by Poynard et al11 suggests that a sustained response is achieved in 14%-22% of cases treated with 3 million international units (miu) of IFα over 6 months, and in 28%-38% of patients treated with the same dose for 12 months or longer. Our estimates of the effectiveness of treatment were based on the assumption of an 18% sustained response rate after IFα treatment for 6 months and a 35% sustained response rate after 12 months' treatment, with both rates subject to sensitivity analysis. Quality of life Chronic HCV infection has been described as largely asymptomatic, with less than 20% of patients developing non-specific symptoms such as fatigue.8 However, recent studies suggest that it has an impact on quality of life.12-14 People with chronic HCV infection scored significantly lower than a comparable but healthy population on various generic health measures, such as the 36-item short-form health survey (SF-36).12 Side effects of treatment: Mild side effects of IFα are common and most patients will experience flu-like symptoms which diminish over time. Less transient effects -- fatigue, irritability, depression, thyroid disease and skin disorders -- are more troublesome and cause some patients to discontinue treatment. Less than 2% of patients will experience severe side effects.8 Quality-adjusted life-years (QALYs): The impact of the disease (including its sequelae and treatment with IFα) on quality of life can be incorporated into the analysis by weighting the life-years gained according to their quality, thus generating an estimate of quality-adjusted life-years, or QALYs. These weights are usually calibrated on a scale of 0 to 1, where 0 is equivalent to death and 1 to a year of life in full health. Subjective impact of the disease: A major shortcoming is a lack of understanding of the subjective impact of the disease. In the absence of patient-generated weights, other authors have used quality-of-life weights based on clinical judgement or small scale surveys.4,6,7 The weights are 0.8-0.95 for chronic hepatitis, 0.7-0.8 for compensated cirrhosis, 0.28-0.5 for decompensated cirrhosis, and 0.1-0.25 for hepatocellular carcinoma. The weights we used were adapted from those derived by Kim et al,7 as these were the only ones based on patient judgement (Table 1). In the baseline case, it was assumed that treatment had no additional adverse effect on quality of life -- an assumption relaxed in the sensitivity analysis. Costs of treatment Estimates of the treatment costs for each of the main clinical endpoints were based on clinical protocols as specified by the National Health and Medical Research Council (NHMRC)15 and the clinical opinion of one of the authors (G C F). The protocols were costed using the Medicare Benefits Schedule for medical services,16 and Australian national diagnosis-related groups (AN-DRG-3.1) for hospital admissions (Table 1).17 See Appendix for details. All costs are in Australian dollars at 1996 prices. Cirrhosis: A weighted cost was computed on the basis of specified treatment protocols for each of the main clinical manifestations of cirrhosis. The weights reflect the estimated proportion of patients likely to experience each state.6 It was further assumed that 2% of patients experiencing cirrhosis would undergo a liver transplant each year and that 25% of cirrhotic patients would experience at least one episode of septicaemia requiring hospital admission. IFα: The unit cost of IFα reflected its price to the healthcare system. It was assumed that treatment would be given at a rate of 3 miu three times a week for either 24 or 48 weeks and would be discontinued in people who did not show a reduction in serum alanine aminotransferase (ALT) levels after 12 weeks. Experience in Australia suggests that 26% of people will fail to respond in this period and will discontinue treatment (R G Batey, Deputy Dean, and Professor of Gastroenterology, Faculty of Medicine and Health Sciences, University of Newcastle, Newcastle, NSW, personal communication). Other costs: Lost production capacity caused by morbidity and premature mortality associated with HCV infection was not considered.18 Other patient costs, such as the use of community services and alternative medicine, were also omitted. This biases the findings against treatment with IFα. Cost effectiveness of IFα treatment The cost effectiveness of treatment for 6 months is expressed as the additional cost per QALY gained over and above no treatment (conventional management). The incremental cost effectiveness of 12 months' treatment over 6 months' treatment is also reported. Future costs and outcomes were discounted at both 3% and 5% (as recommended by Gold et al19). Undiscounted results are also presented and the effect of using a higher discount rate is assessed in the sensitivity analysis. (Discounting is the process whereby costs and benefits occurring at different points in time are made commensurate with each other.) Sensitivity analysis The robustness of the results was examined by sensitivity analysis (given the uncertainties inherent in the modelling approach). Key variables included in the sensitivity analysis were response rates, rates of disease progression, time to develop sequelae, costs of treatment, percentage of patients excluded at 12 weeks, age groups, the discount rate, and the adjustment for quality of life. Back to text 1: Baseline assumptions: values and costs used in the Markov modelValueRangeDisease transition probabilities From chronic infection to cirrhosis20%10%-30% From cirrhosis to advanced liver failure20%10%-30% From cirrhosis to hepatocellular carcinoma14%7%-21%Effectiveness of treatment Long term response after 6 months18%14%-24% Long term response after 12 months35%26%-38% Discontinue treatment after 12 weeks because of lack of response26%13%-39%Health state (quality of life) weights Chronic infection0.950.80-1.00 Cirrhosis0.750.50-0.90 Advanced liver failure0.250.10-0.40 Hepatocellular carcinoma0.250.10-0.40 Treatment with interferon alfa (IFα)0.950.80-0.95 Resolved infection1.001.00-1.00Treatment episode costs*$$Medical management of chronic infection405200-600Treatment with IFα 6 months' treatment including discontinuing treatment2 8001 975-3 630 12 months' treatment including discontinuing treatment5 1503 620-6 670Cirrhosis (weighted average)2 8251 400-4 200 Management of compensated cirrhosis660330-990 Diuretic-sensitive ascites1 880940-2 820 Refractory ascites13 6406 820-20 460 Variceal haemorrhage (Year 1)5 8502 925-8 775 Hepatic encephalopathy (Year 1) 6 3753 190-9 565 Hepatocellular carcinoma (Year 1)8 8654 435-13 290 Liver transplant (Year 1)92 52546 265-138 790 Septicaemia5 3002 650-7 950Terminal care28 40014 200-42 600Back to text 2: Summary of costs and outcomes of interferon treatment for chronic hepatitis C infection in a hypothetical cohort of 1000 patients Treatment durationNet costs ($)Lives saved Life-years savedQALYs gainedUndiscounted(a) 6 months1 185 55512.0176.3 531.4(b) 12 months2 013 84523.4 342.7830.7(c) Increment828 290 11.3166.5299.3Discounted (3%)(a) 6 months1 800 3807.694.2320.1(b) 12 months3 209 34514.7183.2490.9(c) Increment1 408 9657.189.0170.8Discounted (5%)(a) 6 months2 049 6455.763.9237.7(b) 12 months3 694 02011.1124.2359.5(c) Increment1 644 3755.460.3121.8Treatment DurationCost/life saved ($)Cost/ life-year saved ($)Cost/ QALY gained ($)Undiscounted(a) 6 months98 7106 7202 230(b) 12 months86 2355 875 2 425(c) Increment73 0204 9752 765Discounted (3%)(a) 6 months238 52519 1105 625(b) 12 months218 67017 520 6 540(c) Increment197 64515 835 8 250Discounted (5%)(a) 6 months360 37032 095 8 620(b) 12 months334 02029 750 10 275(c) Increment306 120 27 265 13 505 Incremental cost and outcomes (a) 6 months' treatment with interferon v. no treatment; (b) 12 months' treatment with interferon v. no treatment; (c) 12 months' treatment with interferon v. 6 months' treatment. Net costs = costs of treatment minus costs of conventional management of the disease. QALY = quality-adjusted life-year. Back to text 3: Discounted costs of interferon treatment for chronic hepatitis C infection per life-year and per quality-adjusted life-year (QALY) gained under best and worst case scenarios (sensitivity analysis)Treatment for 6 months v. no treatmentCosts ($) per QALY (Baseline = $5 625)Costs ($) per life-year (Baseline = $19 110)VariableRangeBest caseWorst caseBest caseWorst caseRate of cirrhosis10%-30% 3 2409 6459 20548 820Time to cirrhosis (years)10-304 09010 29011 64537 470Rate of sequelaeComposite*5 1156 26512 95037 590 Liver failure10%-30% Hepatocellular carcinoma7%-21%Time to sequelae (years)5-155 4955 77516 21522 970Long term response rateComposite3 3908 26511 68027 600 6 months14%-24% 12 months26%-38%Cost of interferon per dose$13-$393 0358 12010 31027 595Cost of health service useComposite4 0657 18513 81024 410 Chronic infection50%-150% Cirrhosis50%-150% Terminal care50%-150%Discontinue treatment at 12 weeks13%-33%5 2406 01017 81020 415Duration of model (years)20-404 30512 95012 89049 090Discount rate0-10%2 23018 6206 72589 900Quality-of-life weightsComposite (See Table 1)2 08028 03019 110† 19 110†Treatment for 12 months v. 6 months Costs ($) per QALY (Baseline = $8 250)Costs ($) per life-year (Baseline = $15 835)VariableBest caseWorst caseBest caseWorst caseRate of cirrhosis3 80019 8257 02542 270Time to cirrhosis (years)5 21012 6859 32026 455Rate of sequelae6 98010 16510 76531 040 Liver failure Hepatocellular carcinomaTime to sequelae (years)7 8358 72513 49518 970Long term response rate 4 36063 1758 125214 105 6 months 12 monthsCost of interferon per dose 4 15512 3407 91023 475Cost of health service use 5 48511 01010 53521 135 Chronic infection Cirrhosis Terminal care at 12 weeks 6 8109 58513 07518 595Duration of model (years) 7 20017 3009 75541 910Discount rate2 76533 4754 97578 310Quality-of-life weights 7 5309 81015 835†15 835† * Composite refers to the aggregate effect on cost per unit of outcome of changing all subsidiary variables simultaneously. †Quality adjustment has no effect on the number of life-years saved. Back to text Summary points Costs and benefits of healthcare interventions have to be considered in the context of a limited healthcare budget. The cost effectiveness of interferon alfa (IFα) treatment of chronic hepatitis C infection in Australia has improved since it was first evaluated in 1994. The major effect of IFα therapy is on improving quality of life, not life expectancy. More research is required on the impact of chronic hepatitis C infection and IFα treatment on quality of life. Back to text APPENDIX 1 Treatment episode costs Back to article 1: Medical management of chronic infection Resource categoryNumberUnit costTotal Cost Specialist visits2112.65225.30 Pathology Liver function test219.8039.60 Alfa fetoprotein219.9039.80 Ultrasound1101.70101.70 Total 406.40 2: Treatment with interferon (6 months) including workup Resource categoryNumberUnit costTotal Cost Specialist review initial consultation194.1594.15 subsequent consultation647.15282.90 Interferon (allowing for drop out)0.871889.281643.67 Pathology Full blood count717.20120.40 Liver biopsy1130.35130.35 Liver function test719.80138.60 International normalisation ratio112.4012.40 Thyroid function test341.00123.00 PCR380.00240.00 Anti-HCV113.7013.70 Total2799.17 3: Treatment with interferon (12 months) including workup Resource categoryNumberUnit costTotal Cost Specialist review initial consultation194.1594.15 subsequent consultation1447.15660.10 Interferon (allowing for drop out)0.813 755.253 041.74 Pathology FBC1517.20258.00 Liver biopsy1130.35130.35 LFT1519.80297.00 International normalisation ratio112.4012.40 Thyroid function test441.00164.00 PCR680.00480.00 Anti-HCV113.7013.70 Total5151.44 4: Management of compensated cirrhosis Resource categoryNumberUnit costTotal Cost GP visits424.5098.00 Specialist visits initial1110.75110.75 subsequent355.45166.35 Pathology LFT219.8029.60 AFP419.9079.60 Ultrasound283.95167.90 Total662.20 5: Management of diuretic-sensitive ascites Resource categoryNumberUnit costTotal Cost Inpatient admissions0.331980.00653.40 Day-only admissions1455.00455.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Aldactone 200 mg/day199.0699.06 Procedures Paracentesis138.2038.20 Total1882.86 6: Management of refractory ascites Resource categoryNumberUnit costTotal Cost Day-only admissions26455.0011 830.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Norfloxacillin 200 mg/tds0.33545.15179.90 Procedures Paracentesis2638.20993.20 13,640.30 7: Management of variceal haemorrhage - Year 1 Resource categoryNumberUnit costTotal Cost Hospital admission11980.001980.00 Day-only admissions5455.002275.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Propanolol182.4982.49 Procedures Oesophagoscopy (+ anaesthetic)3291.95875.85 Total5850.40 8: Management of hepatic encephalopathy - Year 1 Resource categoryNumberUnit costTotal Cost Hospital admission2.41980.004752.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Lactulose 60 mls1734.96734.96 Procedures Diagnostic endoscopy (+ anaesthetic)1213.75213.75 Paracentesis138.2038.20 Total6376.11 9: Management of hepatocellular carcinoma - Year 1 Resource categoryNumberUnit costTotal Cost Hospital admission (diagnosis)16947.006947.00 Inpatient admission17846.907846.90 Specialist visits initial visit1110.75110.75 subsequent visits955.4555.45 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Procedures Paracentesis138.2038.20 Total8866.60 10: Other hospital admissions Reason for admission/treatmentRateUnit cost ($) Liver transplant (+ associated admissions)0.0292,527 Major infection (septicaemia)0.255,300 Terminal care - Advanced liver failure28,400 - hepatocellular carcinoma28,400 Back to text

Alan Shiell · Sue Brown · Geoff C Farrell

Editorial Shedding light on bowel cancer prevention The time has come for a concerted public education campaign MJA 1999; 170: 244-245 Colorectal cancer (CRC) is the second most common cause of cancer death in Australia.1 While motor vehicle accidents cause one death about every five hours, and breast cancer causes one death every four hours, CRC causes one every two hours. Australia has made a major government-sponsored effort to reduce mortality from motor vehicle accidents, and screening to prevent breast cancer mortality is an accepted government-sponsored initiative. Why then is there still confusion and argument about CRC prevention? There is convincing evidence that finding and removing adenomas in individuals at increased risk for bowel cancer prevents development of subsequent cancer in most.2 This would seem logical given the acceptance of the polyp-cancer sequence.3 In this issue of the Journal, Croese clearly demonstrates the potential for improving mortality.4 Using a community-based open-access colonoscopy service in Townsville, he showed that patients over 50 years of age who had undergone colonoscopy (with polypectomy when necessary) were less likely to be subsequently diagnosed with CRC than the remaining community in the same age group. Most of his repeat-colonoscopy patients had higher than average risk for developing CRC, which he defined as having one or more first-degree relatives with CRC or polyps, or ulcerative colitis, including quiescent pancolitis or active limited colitis. His message is simple: CRC can be prevented if those at increased risk are alerted to the need to enter a colonoscopic surveillance program. The strengths of the study are that it reports the outcome of "real world" colonoscopy practice from a relatively confined geographic area and provides details of cancers occurring during surveillance. The population was isolated, and the author was able to comprehensively cross-check data, making the information particularly valuable. The study's weaknesses -- a heterogeneous, unmatched population and retrospective comparisons -- were comprehensively addressed by the author. Although colonoscopic surveillance of those at higher risk of CRC is justified, surveillance intervals and starting age remain controversial. Timing of repeat colonoscopy will be partly influenced by the possibility of metachronous lesions, although these have been documented to occur in fewer than 1% of patients.5 The age at which to begin colonoscopic surveillance is also debated and, as about 8% of cancers develop in people aged under 50 years, it would not seem reasonable to withhold educational information from this group despite any perceived increase in cost. However, despite the simplicity of the message, many authorities in Australia still disagree on the need to deliver it. We need a coordinated, sponsored public education campaign to inform our community that an important step to reduce mortality from CRC is for those at increased risk (eg, first-degree relatives of people with CRC or polyps) to see a medical practitioner for advice and referral to an appropriate colonoscopic surveillance program. At the moment, the message is confused, as so well illustrated by Ward.6 Can we also shed some light on screening to prevent bowel cancer in the average-risk individual in our community? Setting aside the issue of mass screening for now and focusing on case-finding (ie, giving the appropriate advice to individuals who seek it or who may be receptive to it), there are four options for prevention or, at least, early diagnosis. Screening based on faecal occult blood testing (FOBT) reduces mortality from CRC. Studies showed a 16% reduction in mortality with biennial screening in the United Kingdom7 and Denmark,8 while a 33% reduction was seen with annual screening in the United States.9 Despite this well-designed research, the Australian Health Technology Advisory Committee has recently recommended further pilot studies on the efficacy of FOBT screening in the over-50 years age group. What other evidence they require remains a mystery. Flexible sigmoidoscopy is proposed for screening by many cancer authorities worldwide, usually in conjunction with FOBT. The combined approach recognises the limitations of flexible sigmoidoscopy, which may miss 50% of polyps and CRCs. Several retrospective studies have found that, in patients with proximal colon cancers, only 17%-30% of adenomas are in reach of the flexible sigmoidoscope.10 A prospective colonoscopy study showed that only 35% of 105 patients with proximal colon cancer had adenomas distal to the splenic flexure.11 These studies confirm that rectosigmoid adenomas ("sentinel" polyps) are an insensitive marker for proximal colon cancer, and that most proximal colonic neoplasms are not associated with distal polyps or cancer. These conclusions are supported by recent Australian data.12 Screening by flexible sigmoidoscopy alone would fail to detect 70%-80% of proximal cancers. Addition of annual FOBT would increase the diagnostic yield, but at increased cost. Colonoscopy is the third screening option, but has been criticised because of its cost and the failure to demonstrate that it improves mortality. Croese found that, in people aged over 50 years, the rate of cancer diagnosis in the unscreened population was double that in individuals who had previously had colonoscopy (for whatever reason). Almost half the cancers in the unscreened population were Dukes stage C or D, compared with only 16% in the previous-colonoscopy group.4 Australian data confirm that the cost-effectiveness of colonoscopy at both five- and 10-year intervals is almost identical to that of annual FOBT.13 Flexible sigmoidoscopy, alone or combined with FOBT, was found to be significantly less cost effective. Barium enema remains the fourth cost-effective diagnostic option, although it suffers from the fact that at least 20% of individuals will have a lesion identified which requires subsequent colonoscopy. A cohesive, unified and comprehensive public education campaign about CRC and the potential for its prevention is needed. This should emphasise the common nature of CRC and should target higher-risk groups, who can be offered colonic surveillance. This would be a start in reducing the current high mortality rate. When screening strategies for early diagnosis or prevention of CRC are chosen, compliance, costs and efficacy are all key issues. The fact that we have four effective options now allows the practitioner to offer individuals a menu from which they can select a test, depending on their preference and perceived compliance. Terry D Bolin Associate Professor, Gastrointestinal Unit Prince of Wales Hospital, Sydney, NSW Melvyn G Korman Associate Professor, Gastroenterology Unit Monash Medical Centre, Melbourne, VIC Anti-Cancer Council of Victoria. Canstat 1997; 26: 2. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329: 1977-1981. Cotton S, Sharp L, Little J. The adenoma-carcinoma sequence and prospects for the prevention of colorectal neoplasia. Crit Rev Oncol 1996; 7: 293-342. Croese J. Colorectal cancer after open-access colonoscopy: a community and case survey. Med J Aust 1999; 170: 251-254. Leggett BA, Cornwell M, Thomas LR, et al. Characteristics of metachronous colorectal carcinoma occurring despite colonoscopic surveillance. Dis Colon Rectum 1997; 40: 603-608. Ward M. Preventing colon cancer: the problem with guidelines or The perils of prevention. Med J Aust 1997; 166: 201-204. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472-1477. Kronborg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996; 348: 1467-1471. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328: 1365-1371. Lemmel GT, Haseman JH, Rex DK, Rahmani E. Neoplasia distal to the splenic flexure in patients with proximal colon cancer. Gastrointest Endosc 1996; 44: 109-111. Rex D, Chak A, Sack L, et al. Prospective determination of distal colon findings in patients with proximal colon cancer. Gastrointest Endosc 1998; 47: AB103. Nicholson FB, Stern AI, Korman MG, Hansky J. Colorectal cancer screening -- are proximal polyps missed by using flexible sigmoidoscopy? Digestion 1998 Suppl 3: 730. Bolin TD, Korman MG, Stanton R, et al. Positive cost effectiveness of early diagnosis of colorectal cancer. Colorectal Dis 1999; 1: 2. Reprints: Associate Professor T D Bolin, GI Unit, Prince of Wales Hospital, High Street, Randwick, NSW 2031. More articles on Gastroenterology Reprints: Associate Professor T D Bolin, GI Unit, Prince of Wales Hospital, High street, Randwick, NSW 2031. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Terry D Bolin · Melvyn G Korman

Research Colorectal cancer after open-access colonoscopy: a community and case survey John Croese MJA 1999; 170: 251-254 For editorial comment, see Bolin & Korman Abstract - Introduction - Methods - Results - Discussion - References - Author's Details - - More articles on Gastroenterology Abstract Objective: To evaluate whether colonoscopy protects against subsequent colorectal cancer (CRC). Design: Case and population survey. Setting: Townsville region in northern Queensland, between mid 1985 and January 1998. Subjects: All 8430 patients who underwent 11 148 colonoscopies performed by the author at the Mater Private Hospital (a community-based open-access colonoscopy service) between July 1985 and December 1996; those who were subsequently diagnosed with CRC, to January 1998; and all 476 residents diagnosed with colorectal cancer between 1994 and 1997. Main outcome measures: Age-standardised CRC incidence for 1994-1997 for patients who had had a previous colonoscopy and for the remaining community; Dukes' grade of CRCs. Results: For people aged 50 years and over, the incidence of CRC was significantly lower among those who had had a previous colonoscopy than in the remaining community (1.14 versus 2.31 per 1000 patient-years; P = 0.0046). For people aged 35-49 years, the incidence was 0.35 versus 0.31 per 1000 patient-years (P = 0.86). Thirty-one CRCs developed in 29 people who had had previous colonoscopy; only five of these CRCs were graded Dukes C, with none graded Dukes D. In contrast, almost half the CRCs in the rest of the community were graded Dukes C or D (P < 0.001). All but one of those diagnosed with CRC on repeat colonoscopy had risk factors (personal or family history), and 23 of the CRCs were subclinical, with 20 being diagnosed during surveillance colonoscopy. Conclusions: Patients aged over 50 years who had previously undergone a colonoscopy and ensuing treatment were less likely to be diagnosed with CRC than otherwise expected. Surveillance colonoscopy led to diagnosis of CRCs with lower Dukes grades. Introduction Colorectal cancer (CRC) is the most common internal malignancy and the second most common cause of death from cancer in Australia. CRC incidence in Australia is similar to that in other developed countries,1 but in the US both incidence and mortality are now decreasing.2 This change has been attributed to removal of premalignant polyps, detection of proportionally more early lesions by colonoscopy, and more effective treatment.3 Strategies based on colonoscopic surveillance and targeting people at increased risk of developing CRC are being promoted.3-5 However, colonoscopy, particularly in community-based, open-access practice, has not been shown to reduce CRC mortality. Indeed, although the rate of colonoscopies in Australia has increased fourfold since 1984, the incidence of CRC in New South Wales between 1973 to 1992 continued to increase by 2% per year in men and 0.9% per year in women.6This study aimed to evaluate whether colonoscopy protects against subsequent CRC by comparing CRC incidence and pathological grading between people who have had a previous colonoscopy and the rest of the population in a geographically isolated area. Methods Setting The study was set in Townsville and the surrounding region (defined by the postcodes 4804-4822, 4849 and 4850; Figure 1). Townsville is a regional centre in northern Queensland that provides centralised health services, including colonoscopy, for a population of 198 000 dispersed over 200 000 km2. The nearest alternative colonoscopy services are located at Cairns and Mackay, 400 km distant. Colonoscopy patients Subjects were patients who underwent colonoscopy performed by myself at the Mater Private Hospital, Townsville. All patients who underwent colonoscopy between July 1985 and December 1996 were identified, most from the hospital's detailed computerised records, but some of those examined between 1985 and 1990 from a hospital work ledger which gave only surname and given name. In addition, detailed demographic and clinical information was collected prospectively in a procedural database for all colonoscopy patients from April 1994 to December 1997. Similar information was obtained retrospectively from the case records of 600 randomly chosen patients who underwent colonoscopy between 1986 and 1990. Colonoscopic procedures and surveillance Colonoscopies were performed on patients referred by a general practitioner or specialist either for surveillance or for investigation of symptoms. Through concessions available until mid 1996, the service was equally available to all patients irrespective of financial resources. Fibreoptic colonoscopes were used before 1990, and video colonoscopes after then. Patients were lightly sedated with fentanyl (100 µg) and midazolam (2.5-5 mg). Treatment (eg, polypectomy, CRC resection) was given as necessary. Surveillance recommendations were mostly included in procedure reports and passed to both the patient and the referring doctor. While these recommendations changed over time consistent with published guidelines,3,7 a general summary is: Annual surveillance for either active ulcerative pancolitis of seven years' duration or longer or a previous malignancy plus a family history of hereditary non-polyposis colorectal cancer (HNPCC);3,7 One- to two-yearly surveillance for a previous CRC before 50 years and for those older than 25-40 years with either CRC developing in a first-degree relative before 50 years or a family history of HNPCC; Two- to five-yearly surveillance for longstanding quiescent pancolitis or active limited colitis, CRC or polyps in a first-degree relative, previous CRC, or large (>1 cm diameter) or multiple colonic polyps; and Five- to 10-yearly surveillance, depending on age, for a small adenomatous polyp. Colorectal cancer diagnoses All patients diagnosed with CRC in Townsville between January 1994 and December 1997 were identified retrospectively by searching the computerised databases of all three pathology services, three hospitals, three endoscopy services, three colonoscopists (including myself) and one oncology service provider in Townsville, and from the CRC audits maintained by the six surgeons in Townsville. From 1995, patients diagnosed with CRC were also identified prospectively by clinicians and institutions. Patients diagnosed with CRC who had had a previous colonoscopy performed by myself at the Mater Private Hospital were identified to January 1998. Clinical records of all patients diagnosed with CRC were audited by myself. A modified Dukes classification (A, B, C or D) was used for staging cancer spread.8,9 A malignant polyp was classified separately if colonoscopic resection was regarded as the definitive treatment. In cases of synchronous lesions, the lesion with the most invasive grading was registered. Incidence of CRC Colonoscopy population: The incidence of CRC was calculated as the number of cases per thousand patient-years for the period 1994-1997 for patients who had had a previous colonoscopy and still lived in the region in 1997 (colonoscopy population). Residence was determined from the electoral register current in January 1997,10 which is considered reliable as voter registration is compulsory in Australia. To reduce mismatch errors caused by individuals with identical names, only patients with a known middle name (duplication rate, 0.3%) were cross-referenced against voters who also had a recorded middle name (duplication rate, 1.3%). The number of patients without a middle name who were still resident was estimated and added to the above on the assumption that the proportion still resident would be the same in the groups with and without a known middle name. CRC incidence in each year was calculated for patients who had undergone previous colonoscopy up until the previous calendar year. For example, the incidence of CRC in 1994 was calculated for patients who had undergone previous colonoscopy up to 1993. Age of colonoscopy patients was determined for the year of incidence. The number of patient-years was the total for all patients in a given age range who had previously had a colonoscopy up to 1993, 1994, 1995 and 1996. Community: The incidence of CRC in the remaining population (community) was determined from the number of cases that occurred between 1994 and 1997 in people not registered as a colonoscopy patient per the region's population less the colonoscopy population. Population data were obtained from the August 1996 census undertaken by the Australian Bureau of Statistics.9 Statistical analyses Binary data were compared in two by two contingency tables using chi-squared analyses.12 The age-standardised incidences of CRC in colonoscopy patients versus the community were tested for the hypothesis that the ratios were equal to one.13 Results Colonoscopies From mid 1985 to the end of 1996, I performed 11 148 colonoscopies on 8430 patients (Figure 2). The number increased steadily, from 590 in the 18 months 1985-1986 to 2708 in the two years 1995-1996. The number of repeat colonoscopies increased from 12 (2.0%) in 1985-1986 to 875 (32.3%) in 1995-1996. Clinical and procedural characteristics are summarised in Box 1. Slightly more women than men had colonoscopies. Patients undergoing repeat colonoscopies were an average six years older than those newly referred and were more likely to have had surveillance for increased CRC risk as the primary indication (50.7% of repeat colonoscopies versus 15.0% of first colonoscopies; P < 0.0001). Primary indication also varied with time. For example, an abnormal barium enema was a common indication before 1991 (7.0%), but accounted for few after 1994 (0.3%; P < 0.0001). In contrast, a family history of polyps or CRC accounted for a greater proportion of colonoscopies after 1994 (10.6% of first and 11.2% of repeat colonoscopies) than before 1991 (6.3%; P < 0.0001). From the outset, the caecal completion rate exceeded 95%, and from 1994 it was 98.9% overall and 99.5% in those without a malignant obstruction. Polyps were diagnosed (and removed) in a greater proportion of repeat than first colonoscopies (36.1% versus 29.8%; P < 0.0001). Both these rates were higher than for colonoscopies performed before 1991 (24.5%; P < 0.0001). However, CRC was diagnosed less often in repeat than in first colonoscopies (0.6% versus 2.2%; P = 0.001). Resident populations Complete details, including a middle name, were recorded for 5762 of the 8430 colonoscopy patients (68.4%), and 4200 of these (72.9%) were registered voters and residents of the Townsville region in 1997. A surname and one given name only were recorded for the remaining 2668 patients -- 1913 from the hospital's computer register and 755 from the work ledger. This gave an estimated total number of resident colonoscopy patients of 6195 in 1997. Colorectal cancers Between 1994 and 1997, 476 new CRCs were diagnosed in residents of the Townsville region, with 474 in people aged over 35 years. Eighteen were in patients who had had a previous colonoscopy; each of these was diagnosed per colonoscopy by myself, nine at the study hospital (registered in the procedural database and shown in Box 1), and the remainder elsewhere. Incidences of CRC between 1994 and 1997 are shown in Box 2. In people aged over 50 years, the annual incidence of CRC in the colonoscopy population (1.14) was just less than half that in the remaining community (2.31; P = 0.0046). Between July 1985 and January 1998, I diagnosed 31 CRCs in 29 patients who had had a previous colonoscopy (two patients had a second CRC diagnosed two years after the first in each case). All but one of these patients had a personal or family history that warranted surveillance, and 21 had been enrolled in surveillance programs, with 20 (65%) having had multiple previous colonoscopies (mean, 3.4; range, 2-9). For 20 of the CRCs, planned surveillance was the indication for the repeat colonoscopy. Among the 11 people with symptoms as the primary indication, these symptoms were considered unrelated to the CRC in at least three. The time between most recent previous colonoscopy and diagnosis averaged 37 months (range, 3-136 months). Staging of CRCs is shown in Box 3. Metastatic spread from CRCs was less common in patients who had had a previous colonoscopy than in the community; only five of the 31 cases in colonoscopy patients were graded C, and none were graded D, while 219 of the 458 community cases (48%) were graded C or D (P < 0.001). Among the five colonoscopy patients with metastatic spread (Dukes C), the time between most recent previous colonoscopy and diagnosis was 19, 24, 29, 32 and 70 months, respectively. Discussion The study evaluated a colonoscopic service that followed and promoted contemporary surveillance guidelines similar to those currently recommended by professional cancer and gastroenterological societies.3 The incidence data suggest, but do not prove, that colonoscopic surveillance confers a benefit. Age-standardised incidence of CRC among people aged 50 years and over in the Townsville region was lower among those who had had a previous colonoscopy, along with any treatment considered necessary (eg, polypectomy or bowel resection), than in the community. This was despite the fact that many of those who had had a previous colonoscopy had a personal or family history likely to increase their risk of developing CRC. Furthermore, the CRCs that occurred in those who had had a previous colonoscopy were of a lower Dukes grade than those occurring in the community. The difference in incidence suggests but does not prove that colonoscopy is protective against CRC. CRC incidence for 1994-1997 in those who had had a previous colonoscopy may have been reduced, at least partly, by detection of subclinical CRCs during their pre-1994 colonoscopies. On the other hand, selection bias suggests that these people would develop more CRCs than the general population. The impact of each of these factors could not be measured, and there is no historical benchmark or matched population for comparison of outcomes. However, the result does suggest that colonoscopy confers a benefit, possibly because of removal of polyps and certainly because of detection and treatment of subclinical CRCs. In people aged 35-49 years, CRC incidence in those who had had a previous colonoscopy was similar to that in the community. Without a control group, a benefit of colonoscopy cannot be dismissed, as the colonoscopy group was expected to have higher CRC incidence. However, it is evident that, because of the large number of people aged 35 to 49 years and the low incidence of CRC, surveillance must be targeted to be effective. Polypectomy rate was high, and higher in repeat than in first colonoscopies. This also implies that patients having repeat colonoscopies had increased risk of developing CRC.14 While the high polyp rate may have been due to their older average age,15 the latter would also be expected to increase the CRC rate, which did not occur. Given an expectation that all lesions seen at the previous colonoscopy had been dealt with, this outcome (high polyp versus low CRC rate) validates the selection criteria for surveillance. The higher polypectomy rate after 1994 compared with that before 1990 probably relates to other circumstances, such as a higher caecal completion rate, while both indices probably reflect improved instrument technology. Thirty-one new primary cancers developed in 29 colonoscopy patients, with two-thirds diagnosed by planned surveillance colonoscopy. Metastatic spread occurred in only five of these patients. These findings confirm, firstly, that new CRCs will develop and, secondly, that outcome can be improved through early (subclinical) diagnosis.3,16 The number of cancers diagnosed in patients who had had a previous colonoscopy was of concern and suggested lesions might have been missed in the earlier examination. Colonoscopy, even when performed by an expert, does not identify all small lesions, while adverse conditions sometimes obscure gross pathology.17 Colon morphology, quality of the bowel preparation, instrument capabilities and operator proficiency may also impose limitations.3,18 However, substandard colonoscopy is unlikely to have been responsible. The caecum was reached at a rate exceeding the accepted standard (95%),3 and CRCs were observed in all parts of the bowel, arguing against an operator-dependent blind spot. Possibly, the comparatively large number of CRCs found in people undergoing colonoscopic surveillance was simply the outcome of increasing enlistment of an appropriate, at-risk cohort. Although most sporadic CRCs evolve slowly through malignant transition in a polyp, this sequence is truncated or absent for some sporadic CRCs and for CRCs developing in patients with ulcerative colitis or a genetic predisposition.19 It is unrealistic to imagine that surveillance colonoscopy with polypectomy as necessary will much reduce CRC incidence in such at-risk populations. Indeed, it might conceivably increase apparent incidence by uncovering subclinical CRCs. The results support the current practice of targeting individuals with recognised risk factors for surveillance colonoscopy. However, it is important to explain to patients that surveillance does not provide complete protection and that new CRCs are inevitable. Early diagnosis through repeated testing is the essential component of surveillance-derived protection. References Parkin DM, Pisani P, Ferlay J. Estimates of the world-wide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. SEER Program (National Cancer Institute). Surveillance, epidemiology, and end results (SEER) program. Bethesda, Md: National Cancer Institute, 1973-1992. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594-642. Bolin TD, Korman MG. How can we reduce the incidence and mortality of colorectal cancer [editorial]? Med J Aust 1997; 166: 175-176. Macrae FA. Screening for colorectal cancer, 1996 [editorial]. Med J Aust 1996; 165: 102-105. Bell JC, McCredie M, Coates MS, Armstrong BK. Trends in colorectal cancer incidence and mortality in New South Wales, 1973-1992. Med J Aust 1997; 166: 178-181. Mecklin J-P, Jarvinen HJ, Peltokallio P. Cancer family syndrome. Genetic analysis of 22 Finnish kindreds. Gastroenterology 1986; 90: 328-333. Astler VB, Coller FA. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 1954; 139: 846-851. Dunlop MG. Polyps and carcinoma. In: Shearman DJC, Finlayson N, Camillieri, Carter D, editors. Diseases of the gastrointestinal tract and liver. 3rd ed. New York: Churchill Livingstone, 1997: 1399-1448. Australian Electoral Commission. Elector information access system. Electoral roll information for Queensland. Canberra: Australian Electoral Commission, 1997. Australian Bureau of Statistics. 1996 census of population and housing. Community profile, Canberra: ABS, 1996 (Cat. no. 2020.0). Approximate significance for contingency tables. In: Matthews DE, Farewell VT. Using and understanding medical statistics. 2nd ed. Basel: Karger, 1988: 20-66. The binomial distribution. In: Snedecor GW, Cochran WG. Statistical methods. 8th ed. Ames: Iowa State University Press, 1989: 107-134. Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992; 326: 658-662. Williams AR, Balasooriya BAW, Day DW. Polyps and cancer of the large bowel: a necropsy study in Liverpool. Gut 1982; 123: 835-842. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328: 1365-1371. (Published erratum appears in N Engl J Med 1993; 329: 672.) Rex RK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24-28. Baille J, Ravich WJ. On endoscopic training and procedural competence. Ann Intern Med 1993; 118: 73-74. Kuramoto S, Oohara T. Flat early cancers of the large intestine. Cancer 1989; 64: 950-955. (Received 1 May, accepted 21 Dec, 1998) Author's Details 42 Ross River Road, Townsville, QLD. John Croese, MD, FRACP, Gastroenterologist. Reprints will not be available from the author. Correspondence: Dr J Croese, 42 Ross River Road, Townsville, QLD 4812. Email: jcroeseATmedeserv.com.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Back to text Back to text Back to text Back to text Back to text

John Croese