Digestive system diseases

Lourdes I St George,* Daniel Lin† * Obstetrician and Gynaecologist, Suite 4, 36 Belmore Street, Burwood, NSW 2134. † Paediatrician, Westmead Private Hospital, Westmead, NSW. lourdesstgeorgeATbigpond.com To the Editor: A 33-year-old woman, who had borne five children and had had previous caesarean sections, presented in her eighth pregnancy with worsening malabsorption after biliopancreatic diversion for morbid obesity, performed 3 years earlier. Before surgery, she had weighed about 130 kg (height,161 cm; body mass index [BMI], 46 kg/m2); she had gradually reduced her weight to 67 kg. Her surgery had created intestinal malabsorption resulting from the intestinal bypass and from dietary restriction because of gastroplasty. The physiological stress associated with pregnancy worsened her anaemia from protein and vitamin deficiencies, especially fat-soluble vitamins and calcium. She required frequent hospitalisation for intravenous fluids to compensate for dehydration from vomiting and diarrhoea. She was taking oral iron, folate, vitamin D, a calcium supplement, vitamin B12, and having vitamin K injections. Her total weight gain in pregnancy was poor (from 71 kg to 74 kg). At 32 weeks she presented with premature labour and a persistent low fetal baseline heart rate of 90 beats per minute and an unstable lie. She had an emergency caesarean section and delivered a baby boy with a birth weight of 2095 g (average for gestational age). Apgar scores were 7 and 8 at 1 and 5 minutes, respectively; the baby required ventilation for hyaline membrane disease and phototherapy for jaundice, although his blood profile was normal. His clinical course thereafter was uneventful. Obesity (BMI > 30 kg/m2), has become the epidemic of the 21st century, with one in two Australian women being overweight or obese. 1 Morbid obesity (BMI > 40kg/m2) is associated with a 6–12-fold increase in mortality.2 A multifaceted approach is essential for treatment in all patients with obesity, but unfortunately, medical treatment mostly produces short-term weight loss. Thus, bariatric surgery is being performed more frequently. Biliopancreatic diversion has two components: a limited gastrectomy results in reduction of oral intake, inducing weight loss, especially during the first postoperative year; and the construction of a long limb Roux-en-Y anastomosis with a short common “alimentary” channel of 50 cm length, which maintains weight loss long term. Scopinaro, who pioneered this technique, has published long-term results reporting 72% excess body weight loss maintained for 18 years.3 He documented 239 pregnancies in 1136 patients who had undergone biliopancreatic diversion, 25% of whom had been infertile before the operation. During pregnancy, 20% required parenteral nutrition and had fetuses that were small for gestation age. The women had a mean weight gain of 6 kg during their pregnancies, and 80 % delivered babies at term with a mean birth weight of 2.8 kg. 4 From the patient’s perspective, the great advantage of biliopancreatic diversion is the ability to eat a normal diet and still achieve excellent, long-term weight loss. The most serious potential complication is protein malnutrition, with a need to take supplemental calcium and vitamins, particularly vitamin D, lifelong. Because of this potential for significant complications, patients who have had biliopancreatic diversion require lifelong follow-up and pregnancy should be avoided. Ideally this operation should be performed in women who have completed their childbearing.

Lourdes I St George · Daniel Lin

If Indigenous Australians are at high risk of H. pylori infection, the associated risks of peptic ulceration and gastric cancer may make screening and treatment necessary Interest in asymptomatic Helicobacter pylori infection seems largely to have waned in much of the developed world.1-3 It is almost universally accepted that H. pylori causes chronic gastritis and peptic ulcer disease,1-3 and the evidence that the infection also causes gastric adenocarcinoma is virtually unassailable.1-4 In high-risk populations, at least, prevention of gastric cancer by H. pylori eradication is theoretically feasible, although convincing clinical-trial evidence is lacking.2-5 However, perhaps because the incidence of gastric cancer is steadily declining in developed nations (and because H. pylori infection seems to be much less often acquired these days), interest in its prevention remains remarkably low key.1,2 Australian Aboriginals and Torres Strait Islanders are much more likely to suffer ill health and die at a younger age than non-Indigenous Australians.6 However, one health scourge that the Indigenous population seemed to have missed, despite their lower socioeconomic status, was H. pylori infection and its complications.7 For example, seroprevalence studies suggested H. pylori infection was very rare.7 The report by Windsor and colleagues in this issue of the Journal (page 210) is at variance with these earlier findings,8 and strongly suggests that H. pylori infection is as common in Australia’s Indigenous population as it is in developing countries in South America, Africa and parts of Asia.3 If confirmed, these findings may have major health implications; indeed, the high prevalence identified in children8 implies a public health risk which will continue long into the future unless this situation is rectified. Notably, the findings of Windsor et al are limited to a small and possibly unique Indigenous group, and may not be more widely generalisable — more data are needed. However, the fact that over half the population in the remote rural communities studied were tested gives some confidence that H. pylori is remarkably widespread in this community (where 91% were found to be infected by means of a “gold standard” test). On the other hand, in urban Perth, referral bias can not be ruled out as accounting for the high H. pylori prevalence (60%), although the burden of infection remains strikingly high — if bias is the sole explanation, it would have to be particularly pervasive. What are the potential implications of these findings? Gastric adenocarcinoma remains a major health problem in the developing world.2 In the developed world, the consequences of H. pylori infection have arguably been underappreciated. In the United Kingdom, it has been calculated on the basis of relatively conservative assumptions that by age 85, and allowing for competing causes of mortality, the cumulative risk of dying from gastric cancer arising because of H. pylori infection is a staggering 1 in 51 for men and 1 in 96 for women.9 Data from the Northern Territory suggest that the rate of mortality from gastric cancer among Indigenous people has not increased.10 However, gastric cancer may become a much greater burden for the Indigenous population if, as is hoped, life expectancy improves from the current unacceptable median age at death of just 51 years.6 Older studies have suggested that peptic ulcer is uncommon in the Indigenous population,8 but, if Indigenous people undergo fewer endoscopies, this impression might be driven purely by referral bias. It has been calculated that, in the UK population, 1 in 154 men and 1 in 173 women die from peptic ulcer caused by H. pylori.9 The ulcer rates may, however, be truly low in Indigenous Australians, as undernutrition and lower socioeconomic status are associated with lower gastric acid secretion. This allows H. pylori to spread throughout the stomach (causing pan-gastritis and increasing the risk of cancer if people live long enough), but protects against ulcer disease.2,3 Circulatory disease, particularly ischaemic heart disease, is a major cause of mortality in the Indigenous population.6,10 Is H. pylori an important and modifiable risk factor for ischaemic heart disease? Unfortunately, the evidence for this is mixed and, at best, equivocal.11 Overall, widespread eradication of H. pylori to try to reduce ischaemic heart disease in this population is not currently justifiable. Other health problems in the Indigenous population just might be attributable to H. pylori, at least in part. Indigenous Australians have been reported to be more likely to give birth to infants who are small for gestational age,12 and H. pylori infection has been associated with growth restriction in young children.13 A Sydney study also found (among 448 pregnant women attending for routine examinations in the third trimester) that intrauterine growth restriction was twice as common in H. pylori-seropositive women than in seronegative women.14 This association was not explained by smoking or maternal height, although these were also independent risk factors for intrauterine growth restriction.14 While the data clearly need confirmation, the general health risks of a high carriage rate of H. pylori in Indigenous people may have been underestimated and may be another antenatal risk factor. Might H. pylori offer protection from some other diseases, and, if so, might attempts at its widespread eradication lead to more ill health in the Indigenous population? Such concerns have been raised,15 but seem overexaggerated and unlikely. In particular, recent data suggest that H. pylori eradication in peptic ulcer disease neither provokes reflux oesophagitis nor aggravates symptoms of gastroesophageal reflux.16 We need large, population-based intervention trials to define any risks, but whether it is wise to wait for such results before actively intervening remains debatable. H. pylori may be very common in Indigenous Australians, particularly among those living in remote parts of Australia. Future research needs to focus on the prevalence of H. pylori (and strains of different virulence) and the burden of dyspepsia in these populations. Although the exact route of transmission of H. pylori remains controversial, close contact within families is probably at least one key risk factor, and faecal–oral spread is feasible.2,3 Thus, strong consideration needs to be given to trying to reduce the acquisition of the infection in Indigenous children by reducing family crowding, and providing adequate sanitation and clean water. Doctors need to be aware that there may be a high risk of H. pylori infection in subpopulations within Australia. They should consider testing and treating Indigenous patients who present with dyspepsia (or non-ulcer dyspepsia), have a history of peptic ulcer complications, or have a family history of gastric cancer.2,3,17 However, to reduce the disease burden of H. pylori in the next 50 years, population screening and treatment may be the only solution. Assuming the data of Windsor et al are generalisable, a randomised controlled trial to test the health benefits (and risks) of population-based screening and antibiotic treatment in Indigenous Australians should be a government research-funding priority.

Nicholas J Talley MD, PhD, FRACP

Objectives: To determine and compare the prevalence of Helicobacter pylori in an urban and a remote rural Western Australian Indigenous community.Design: Cross-sectional study of Helicobacter pylori status determined by urea breath tests between mid-January 2003 and the end of June 2004.Participants: 520 self-selected fasting participants, comprising 270 members of the Martu community at Jigalong, Punmu and Parnngurr in the East Pilbara region (129 men, 141 women; age range, 2–90 years) and 250 people from the Perth Indigenous community (96 men, 154 women; age range, 3–75 years.Results: The overall prevalence of H. pylori was 76%, but the prevalence in the remote rural community was 91%, compared with 60% in the urban community. The odds of having H. pylori were six times greater for rural than for urban participants (odds ratio [OR], 6.34; 95% CI, 3.89–10.33). Further, the overall odds of H. pylori infection in males (rural and urban combined) were greater than for females (OR, 1.61; 95% CI, 1.02–2.54). In both communities, the prevalence of infection remained relatively constant after the age of 10.Conclusions: The prevalence of H. pylori in the two Indigenous communities was two to three times higher than that in the non-Indigenous Australian population and higher than that shown in previous studies in Indigenous Australians.

Helen M Windsor PhD · Susan D Morrow BA · Barry J Marshall FRACP · Emmanuel A Abioye-Kuteyi MB BS · Jacqueline M Leber RN · Max K Bulsara MSc

Clinical records Patient 1 In 2004, a 63-year-old woman presented to the emergency department with a 1-month history of nausea and intermittent vomiting. Three weeks before presentation she was empirically prescribed esomeprazole for management of dyspepsia. A week before presentation, she stopped taking this medication, as she suspected it was exacerbating the malaise, nausea and vomiting. On presentation, she was pale, with blood pressure of 160/60 mmHg and no signs of fluid overload. Dipstick urinalysis showed blood +, protein ++, and leukocytes. Serum creatinine level was 1878 μmol/L (reference range [RR], 60–125 μmol/L), and serum urea level, 42 mmol/L (RR, 2.5–6.5 mmol/L). A normochromic, normocytic anaemia was present (haemoglobin level, 87 g/L; RR, 130–180g/L), with no eosinophilia. Urine microscopy revealed isomorphic red blood cells, some white blood cells, but no casts. Urine culture showed no growth. On admission, the patient’s remaining medications (irbesartan [150 mg daily] and atorvastatin [40 mg at night]) were also withdrawn as a precautionary measure. As acute interstitial nephritis was suspected, she was treated with methylprednisolone (500 mg daily for 3 days) followed by oral prednisone (50 mg daily). Supportive haemodialysis was begun. On Day 4 of admission, a renal biopsy was performed; results were consistent with acute interstitial nephritis. Prednisolone therapy was continued for a total of 4 weeks on a tapering dose. Supportive dialysis was required for 4 days, by which time renal function had improved. However, at follow-up 8 months later, serum creatinine level remained abnormal at 187 μmol/L (Box 1). Patient 2 In the same year, a 63-year-old man presented to the emergency department with a 3-week history of nausea, vomiting, weight loss and oliguria. Five weeks before presentation, he was prescribed rabeprazole by his family physician as empirical treatment for nausea and dyspepsia. This was replaced by esomeprazole a week later, as symptoms had not resolved. The patient discontinued the latter after 2 weeks’ therapy (12 days before presentation), as he had still gained no relief of symptoms. Medications on presentation were irbesartan/hydrochlorothiazide (300/12.5 mg daily), amlodipine (10 mg daily) and rofecoxib (12.5 mg daily) as required. He had been taking these medications for the previous 3 years, but used rofecoxib infrequently. On presentation, the patient was pale, with no signs of fluid retention. Dipstick urinalysis showed blood ++, protein +, and trace leukocytes. Serum creatinine and urea levels were 1110 μmol/L and 31 mmol/L, respectively. Six months previously, serum creatinine level had been 109 μmol/L. The patient also had normochromic, normocytic anaemia (haemoglobin level, 90 g/L), with no eosinophilia. Urine microscopy revealed isomorphic red blood cells, granular casts, hyaline casts, some white blood cell casts, but no red blood cell casts. Urine culture showed no growth. A clinical diagnosis was made of acute interstitial nephritis induced by a proton-pump inhibitor (PPI). The patient was admitted to hospital and treated with prednisolone (60 mg daily). Renal biopsy 2 days later confirmed acute interstitial nephritis (Box 2). Renal function improved after admission, and serum creatinine level was 600 μmol/L on discharge 5 days after presentation. Subsequently, renal function declined slowly, and, 9 months after presentation, long-term peritoneal dialysis was begun. In these two cases of acute interstitial nephritis, esomeprazole was implicated as the likely causative agent (although Patient 2 was also briefly exposed to rabeprazole). In both cases, renal function improved after esomeprazole was withdrawn and corticosteroid treatment begun, although Patient 2 went on to require long-term dialysis. Omeprazole was first implicated as a cause of acute interstitial nephritis in 1992.1 Since then, 22 case reports of omeprazole-induced acute interstitial nephritis have been referenced in Medline. 2-7 Recently, pantoprazole and lansoprazole have also been implicated as causes of acute interstitial nephritis, 3,8 along with rabeprazole (unpublished data from our centre). Before the cases reported here, the Adverse Drug Reactions Advisory Committee (ADRAC) had been notified of four cases of acute interstitial nephritis induced by esomeprazole, along with six cases of acute renal failure and two of renal impairment. In October 2004, the manufacturer of esomeprazole, AstraZeneca, reported being aware of at least 15 cases worldwide of acute interstitial nephritis possibly induced by esomeprazole, and at least 200 cases worldwide induced by omeprazole (data on file, Astra-Zeneca). Two of these esomeprazole cases and 20 of the omeprazole cases were from Australia (it is unclear whether these two esomeprazole cases were included in those notified to ADRAC). MIMS online lists acute interstitial nephritis as a complication of omeprazole but not esomeprazole.9 A recent hospital series reported drug-induced acute interstitial nephritis as the cause of biopsy-proven acute renal failure in 8% of cases, with PPIs accounting for eight of the 14 cases. 2 The diagnosis of acute interstitial nephritis is most common when renal biopsy is performed for unexplained renal impairment, with a reported prevalence in this setting of 27%.10 PPI-induced acute interstitial nephritis poses a particularly difficult diagnostic challenge, as symptoms are non-specific and may mimic the original indications for which the PPI was prescribed. Most patients diagnosed with PPI-induced acute interstitial nephritis recover renal function, but some fail to recover fully and, in extreme cases, require long-term renal replacement therapy, 2 as in Patient 2. Little is known about the relationship between the risk of PPI-induced acute interstitial nephritis and duration and dosage of PPI therapy, delay in diagnosis, or other factors. In addition, it is not clear whether the prognosis differs between acute interstitial nephritis induced by PPIs and that induced by other drugs. Although both our patients were treated with corticosteroids, evidence for their use remains anecdotal and is not derived from randomised controlled trials. A recent report of the largest retrospective series published to date found no statistically significant difference in outcome, as determined by serum creatinine level, between patients who received corticosteroid therapy and those who did not at 1, 6 and 12 months after presentation.11 PPIs are now the third most commonly prescribed drug in Australia. Although acute interstitial nephritis is a rare complication, it is a potentially catastrophic cause of acute and chronic renal failure. All medical practitioners need to be aware of this potential class reaction. Early recognition may prevent the development of irreversible renal injury. Lessons from practice Acute interstitial nephritis is a rare but serious adverse effect of proton-pump inhibitor (PPI) therapy, which may potentially lead to chronic kidney failure. Acute interstitial nephritis has now been described in association with all PPIs currently marketed in Australia. The initial symptoms of PPI-induced acute interstitial nephritis are usually non-specific, often mimicking the symptoms of dyspepsia for which the PPI was initially prescribed. A high index of suspicion is needed, and serum creatinine level should be checked promptly if the diagnosis is suspected. 1 Serum creatinine level over time after presentation in Patient 1 Shaded area indicates the reference range, 60–125 μmol/L. 2 Renal biopsy specimen in Patient 2 Biopsy specimen from the renal cortex taken 2 days after presentation, showing an interstitial inflammatory infiltrate composed of lymphocytes and eosinophils (I), with mild acute tubular necrosis and a cellular cast (C). (Original magnification × 40; haematoxylin–eosin stain.)

Nimeshan Geevasinga BSc · Lukas Kairaitis FRACP · Gopala K Rangan FRACP · Patrick L Coleman MRCI, FRACP

Constipation is common in children, with prevalences ranging from 0.3% up to 28%. In most children, constipation is functional (ie, without objective evidence of a pathological condition). Painful defecation has been proposed as the primary precipitant of functional faecal retention in early childhood. Faecal soiling is often secondary to constipation, and may occur during spontaneous relaxation of the sphincters precipitated by rectal distension. Management in general practice combines behavioural modification techniques with prolonged courses of laxatives. Treatment is usually successful, but may take up to 6–12 months. Significant numbers of children with initially good responses to therapy for constipation relapse in the long term. Long-term relapse is more frequent in children under 4 years at onset of symptoms and in whom there is a history of faecal soiling associated with constipation.

Anthony G Catto-Smith MD, FRACP

A 68-year-old woman presented with cholelithiasis and common bile duct obstruction. Laboratory tests showed leukocytosis and raised serum alkaline phosphatase levels, but the eosinophil count was normal. Faecal microscopy was not performed. A roundworm (Ascaris lumbricoides) trapped in a T-tube Removal of the stones by means of endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy was unsuccessful because of difficulty catheterising and visualising the ampulla of Vater. After open cholecystectomy and exploration of the common bile duct, the sphincter of Oddi was dilated with bile duct dilators, and a T-tube was inserted before closure. After an uneventful postoperative period, the T-tube was removed 14 days after operation. A dead Ascaris lumbricoides roundworm was trapped in the T-tube. The patient was discharged 2 days later after receiving anthelmintic treatment. Abdominal ultrasound and stool examinations showed no abnormalities at follow-up after 1 month and 6 months. A. lumbricoides, the most common roundworm infecting humans, is endemic in areas where sanitation standards are poor. Adult worms normally reside in the upper gastrointestinal tract, but can migrate into any organ in the body, including the biliary tree (biliary ascariasis).1

Ilyas Baskonus MD · Gokturk Maralcan MD · Abdullah Serin · Necdet Aybasti MD

We present a rare case of spontaneous intramural oesophageal perforation after the rapid ingestion of a cold carbonated beverage. A previously well patient presented with sudden onset of severe retrosternal pain associated with pain on swallowing. A contrast computed tomography scan and gastroscopy confirmed the diagnosis. With the widespread popular practice of drinking cold carbonated beverages, especially during the summer season, clinicians should be aware of this possible serious complication. Clinical recordA 57-year-old woman presented to the emergency department with retrosternal chest pain of sudden onset immediately after the isolated intake of a large mouthful of cold carbonated beverage directly from the bottle. The initial severe pain led to a brief loss of consciousness. The pain was continuous, exacerbated by swallowing, and accompanied by mild nausea, but no vomiting. She was previously a fit, healthy woman with no past medical history relevant to the case. She was febrile (37.6oC) and distressed by the pain. Examination was normal except for epigastric tenderness with retrosternal radiation. There were no signs of peritonism. The only abnormality in the patient’s blood tests was a mildly elevated white cell count of 11.7 3 109/L (reference range, 4.0–11.0 3 109 cells/L). An electrocardiogram and chest x-ray were normal. These initial investigations ruled out a cardiovascular condition, spontaneous pneumothorax, peptic ulcer disease and pancreatitis. The differential diagnosis was oesophageal pathology, including perforation. A computed tomography (CT) scan of the thorax showed a tiny bubble of gas either within the wall of the oesophagus or just adjacent to it in the middle mediastinum (this did not definitively exclude a full perforation of the oesophagus). The patient was admitted and managed with nil by mouth, intravenous fluids, triple intravenous antibiotic therapy (ampicillin 1 g four times a day, gentamicin 5 mg/kg daily [with subsequent doses titrated according to drug level], metronidazole 500 mg twice a day), intravenous omeprazole 40 mg three times a day, and frequent observation. Her fever resolved within 24 hours, but her C-reactive protein level rose to 18.2 mg/L (reference range, 0–8.0 mg/L). A second CT scan, with water-soluble contrast, showed intramural contrast with no extravasation, consistent with a partial perforation of the oesophagus (Box 1). Gastroscopy revealed a 10 cm longitudinal mucosal/submucosal tear in the left posterolateral wall of the oesophagus 3 cm above the gastro-oesophageal junction (Box 2A), and a small sliding hiatus hernia. The rest of the oesophagus, stomach and duodenum were normal. The patient’s symptoms improved with conservative treatment. She started clear fluids on Day 4, progressed to a soft diet, and was discharged on Day 7 with a prescription for oral omeprazole 40 mg daily. After 4 weeks, she still had occasional mild discomfort on swallowing. A repeat gastroscopy showed the healed scar of the tear, with no evidence of stricturing (Box 2B). Gastroscopy also revealed uncoordinated peristalsis of the oesophagus, but video fluoroscopy excluded dysmotility. DiscussionSpontaneous oesophageal perforation (Boerhaave’s syndrome) was first described by the Dutch physician Hermann Boerhaave in 1724.1 The classical presentation follows forceful vomiting. Boerhaave’s syndrome is a form of barogenic rupture caused by a rapid rise in intraluminal pressure when there is sudden distension of the oesophagus in a closed space.2-4 In this case, we postulate that the rapid ingestion of the cold beverage led to spasm of the distal oesophagus followed by effervescent expansion, resulting in a sudden build-up of intra-oesophageal pressure. A similar case, in which a healthy 67-year-old man sustained two oesophageal tears after rapidly ingesting a cold Alka-Seltzer beverage, has been reported by Oriscello and Mahal.5 The vast majority of perforations occur in the left lateral wall of the distal oesophagus, 3–6 cm above the gastro-oesophageal junction, as this part is particularly weak.2,3 Although Boerhaave’s syndrome is relatively uncommon, it is a serious disorder. Weakening of the oesophageal wall (in conditions such as reflux oesophagitis, infectious oesophagitis, Barrett’s ulceration, benign stricture, oesophageal carcinoma, dysmotility and neurogenic abnormalities) predisposes to this syndrome.4,6 Among people who experience complete perforation, mortality is 13%–25% if treated within 24 hours of symptom onset, 33%–65% if treated 24–48 hours after onset, and 89% if treated after more than 48 hours.3,6 The clinical features of Boerhaave’s syndrome range from a subtle presentation to cardiovascular collapse. Complications include septicaemia and shock.2,4,7 The most common symptom is retrosternal chest pain. Associated symptoms include dysphagia, odynophagia, pleuritic chest pain and dyspnoea.2 Examination reveals fever in 50% of patients, subcutaneous emphysema in up to 60%, and the Hamman’s sign of pneumomediastinum in 20% (ie, a crunching sound with each heartbeat).2 Pneumothorax and pleural effusion are more likely to be revealed on investigation than on physical examination. Blood tests are usually normal, apart from leukocytosis in up to 85% of patients.2 An erect chest x-ray may show subcutaneous emphysema, pneumomediastinum, mediastinal widening, mediastinal air–fluid levels, pleural effusion, pneumothorax and/or hydropneumothorax.4,6 However, a chest x-ray is normal in 12%–33% of patients.6 With a high suspicion of oesophageal rupture, an oesophagram with water-soluble contrast should be requested, with progression to barium if the former is negative. However, contrast studies can have false negative results in more than 10% of patients.6,7 A CT scan may show pneumomediastinum, abscess cavities adjacent to the oesophagus, or an actual communication between the air-filled oesophagus and an adjacent mediastinal or paramediastinal air–fluid collection.4,7 Gastroscopy can be diagnostic, but should not be performed routinely, as it can increase the size of the rupture.3,7 If a pleural effusion is present, aspiration by thoracocentesis may show food particles and squamous cells from saliva. The aspirated fluid may have pH < 6 and a high amylase content.6,7 Conservative management can be tried in patients with intramural tears or stable transmural ruptures. Otherwise, surgical treatment should be sought.6 The case we describe here is typical of Boerhaave’s syndrome with partial perforation in terms of the presentation of retrosternal chest pain, odynophagia, fever, leukocytosis and normal chest x-ray, but unusual in its association with carbonated beverage ingestion rather than vomiting. In cases like this, it remains vital to conduct further investigations to rule out a full perforation, for which the presentation may be similar but the outcome rapidly fatal. The role of gastroscopy is controversial, but we chose in this case to use a gentle procedure to confirm the diagnosis. 1 Contrast computed tomography scan of the thorax The scan shows intramural contrast in the oesophagus (arrow) with no extravasation. 2 Gastroscopic images of the oesophagus A: Initial gastroscopy revealed a 10 cm tear in the left posterolateral wall. B: Healed scar of the tear after 4 weeks.

Hui Jern Loh MB BS (Hons) · David A P Cooke MS, FRCSE, FRCS

Gastroenteritis in children is still a common reason for consulting a general practitioner and for hospital admission. Rotavirus is the most common cause of gastroenteritis in children and accounts for half of all hospital admissions for severe acute infectious diarrhoea. Most children with gastroenteritis do not develop dehydration and can be treated at home. Children with mild to moderate dehydration should be treated with low osmolarity oral rehydration solutions, and those with severe dehydration or shock need to be admitted for administration of intravenous fluids. Lactose-free feeds should not be routinely used after acute gastroenteritis, but there is some evidence that a lactose-free diet may reduce the duration of diarrhoea. Antimotility drugs are rarely indicated in children with gastroenteritis, as the potential risks outweigh the benefits. The development of a rotavirus vaccine would provide huge public health benefits and cost savings. Other preventive strategies include educating people about personal and food hygiene and encouraging breastfeeding.

Elizabeth J Elliott MD, FRACP, FRCPCH · Jacqueline R Dalby-Payne MB BS, PhD, FRACP

Kevin B Orr Surgeon, 3/22 Belgrave Street, Kogarah, NSW 2217. stgeorgedermATbigpond.com To the Editor: I report the case of an unexpected complication of a common cardiothoracic procedure which deserves the attention of the general medical community. An 82-year-old general practitioner required coronary artery bypass surgery. Although retired, he was fit enough to continue visiting patients in a number of nursing homes, and occasionally assisted at operations. His condition after the surgery was good for a few days, but deteriorated, with the development of dyspnoea, shortly before he was due to be transferred to a rehabilitation unit. Whether it was realised that his haemoblobin level had fallen from 150 g/L to 90 g/L over the days before surgery is not known. A blood count several days after surgery revealed a haemoglobin level of 100 g/L. This low level was attributed to insufficient transfusion during surgery. The patient was given two units of blood, which raised the haemoglobin level to 120 g/L. Although a repeat test on the day he was discharged to a rehabilitation unit showed the level was again 100 g/L, this result was not seen by a clinician before the transfer. On arrival at the rehabilitation unit, the patient was unable to complete the scheduled activities. He was breathless, returned to his room, almost fainted and had to be helped back into bed. Later that night, he had massive melaena and died. For some weeks leading up to the bypass surgery, the patient had suffered from dyspepsia and was “living on” antacid. He mentioned this to his general practitioner, who did not initiate any investigations or treatment. On the patient’s admission to hospital, the medical officer prescribed omeprazole, presumably in response to the history of dyspepsia. Whether this doctor was aware of a preoperative drop in haemoglobin level is not known. The most likely cause of this man’s death was a bleeding duodenal ulcer exacerbated by coagulation defects associated with major surgery (no autopsy was performed). Bleeding was initially slow but culminated in a fatal haemorrhage. The lesson from this case is that any suggestion of a serious concurrent illness should be thoroughly investigated before major surgery. In this case, a simple gastroscopy before the bypass surgery might have been lifesaving.

Kevin B Orr

Objectives: To determine the response to colorectal cancer (CRC) screening by colonoscopy, through direct invitation or through invitation by general practitioners.Design and setting: Two-way comparison of randomised population sampling versus cluster sampling of a representative general practice population in the Australian Capital Territory, May 2002 to January 2004.Intervention: Invitation to screen, assessment for eligibility, interview, and colonoscopy.Subjects: 881 subjects aged 55–74 years were invited to screen: 520 from the electoral roll (ER) sample and 361 from the general practice (GP) cluster sample.Main outcome measures: Response rate, participation rate, and rate of adenomatous polyps in the screened group.Results: Participation was similar in the ER arm (35.1%; 95% CI, 30.2%–40.3%) and the GP arm (40.1%; 95% CI, 29.2%–51.0%) after correcting for ineligibility, which was higher in the ER arm. Superior eligibility in the GP arm was offset by the labour of manual record review. Response rates after two invitations were similar for the two groups (ER arm: 78.8%; 95% CI, 75.1%–82.1%; GP arm: 81.7%; 95% CI, 73.8%–89.6%). Overall, 53.4% ineligibility arose from having a colonoscopy in the past 10 years (ER arm, 98/178; GP arm, 42/84). Of 231 colonoscopies performed, 229 were complete, with 32% of subjects screened having adenomatous polyps.Conclusions: Colonoscopy-based CRC screening yields similar response and participation rates with either random population sampling or general practice cluster sampling, with population sampling through the electoral roll providing greater ease of recruitment.

Mike Corbett FRACP · Sharon L Chambers RN, GradDipNurs · Bruce Shadbolt PhD · Doug Taupin PhD · Lybus C Hillman MD, FRACP

To the Editor: Duggan’s recent article on coeliac disease1 is a timely reminder of the complex manifestations of this common but under-recognised condition. I write as a patient diagnosed with coeliac disease at the age of 80. Throughout my life I have had aphthous ulcers, all sorts of abdominal pains, diarrhoea and constipation, dermatitis herpetiformis and profound fatigue. The extraordinary fact is that — apart from missing the diagnosis myself — I come from a medical family and have worked in a variety of medical environments both in Australia and overseas. My physique and weight were obviously substandard. Over the years, I consulted many physicians, surgeons and general practitioners. They diagnosed hiatus hernia (a fundoplication was done), gallstones (a cholecystectomy was done), irritable bowel syndrome, and, of course, psychoneurosis. I consulted three gastroenterologists, two of whom performed gastroscopy but did not take a duodenal biopsy. As I entered the rooms of a fourth, the secretary said, “I know your diagnosis” — and she was right. A duodenal biopsy showed flattening of the villi. Since going on a gluten-free diet, I have gained weight, the pains have gone, and the rash and ulcers have not recurred. A second biopsy, performed 6 months later, revealed restoration of the intestinal surface to its normal appearance. Not only is it a disease of malabsorption, but also one of malnutrition. This accounts for its widespread manifestations. Brain and nerve cells require adequate nutrition, just as any other cells of the body. I found, at times, difficulty in focusing attention, comprehension and cognitive processing. The spoken and printed word were meaningless on occasions. The fatigue was sometimes overwhelming. Galen first described the illness in 2 ad, but it took Dicke, a Dutch paediatrician, to trace the culprit to gluten in 1950. He found that children with coeliac disease fared better than usual when deprived of wheat during the Occupation. Other grains subsequently found to contain gluten were barley, rye and oats. Duggan points out that coeliac disease, like syphilis, is a great imitator. Not only is it a condition that can vary widely in its ramifications, it is the only illness treated by lifelong diet restriction. A pathologist colleague, diagnosed at a late age like myself, shares with me the fear of developing lymphoma — a not uncommon sequel to untreated coeliac disease.

William Woods

Objective: To assess the attitudes of final-year medical students to digital rectal examination (DRE) and their experience of performing DRE during clinical training.Design: Questionnaire-based survey.Setting and participants: All students in the final year of medical school at the University of Melbourne in 2003.Outcome measures: Agreement with statements about attitude to DRE; number of DREs performed and abnormalities palpated; and ratings of frequency of supervision and perceived barriers to performing DRE.Results: 222 of 256 students (87%) responded. Almost all (97%) believed that DRE is an essential requirement for a medical practitioner, and 94% that they should have the skill before graduating, while 92% said they had been taught how to perform it. The median number of DREs performed was two, with 17% of students performing none. Sixty-three per cent had palpated a prostate, 24% a prostate cancer, 19% a rectal tumour, and 11% faecal constipation. Half the students (52%) felt they could give a reasonable or confident opinion based on their DRE findings. The most often cited reason for not performing DREs was the lack of a doctor to act as a supervisor.Conclusions: A concerted effort is needed from academics, supervising doctors and students to improve medical students’ proficiency in performing DRE and confidence about their findings.

Nathan Lawrentschuk MB BS · Damien M Bolton FRACS, MD, BA

Geoffrey M Forbes,*† Matthew J Zimmerman, † Brendan J Collins,† John T Edwards† * Head, † Gastroenterologist, Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, WA. geoff.forbesAThealth.wa.gov.au To the Editor: The editorial by Viiala and Olynyk on screening flexible sigmoidoscopy (FS)1 is a welcome reminder that there are alternative colorectal neoplasia (CRN) screening strategies to the Australian National Health and Medical Research Council’s preferred option of annual faecal occult blood testing. The availability of tests for CRN screening raises the issue of whether screening tests should be dictated by government or professional bodies, or requested by the consumer. FS and colonoscopy remain potential alternatives to faecal occult blood testing in Australia, as reflected by US screening guidelines2 and recent local data.1,3 However, it is unreasonable for Viiala and Olynyk to compare the risks of screening FS (generally diagnostic only) in average-risk subjects (perforation rate, 1/50 000) with the risks of colonoscopy (both diagnostic and therapeutic) in Western Australian tertiary hospital outpatients with symptoms or other risk factors for CRN (perforation rate 1/1000). Firstly, it is important to recognise that the perforation risk associated with screening FS comes not just from the diagnostic screening test (1/50 000), but also from follow-up colonoscopy and subsequent polypectomy in patients with distal adenomas seen on FS. Secondly, in the WA tertiary hospital cohort,4 the estimated perforation rate for diagnostic colonoscopy is about 1/2800 (and about 1/420 for colonoscopy accompanied by polypectomy). Asymptomatic subjects having screening colonoscopy are likely to have a lower risk than patients with symptoms or other significant comorbidities having investigative colonoscopy. Recent data from colonoscopic screening programs (which include subjects having polypectomy) have shown an overall perforation rate of less than 1/3000.5 Medical practitioners arranging colonoscopy, and people having this procedure, should be informed about the risks involved and, importantly, be aware that these risks are likely to vary according to the setting in which colonoscopy is performed.

Geoffrey M Forbes · Matthew J Zimmerman · Brendan J Collins · John T Edwards

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

Michael Thomsen · Luis Vitetta · Avni Sali · Matthias Schmidt

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

Fiona J Cumming · Larry Kelly

Consensus is yet to be reached on the optimal approach to screening Australians have a 1 in 21 lifetime risk of developing colorectal cancer.1 The incidence of the disease and mortality resulting from it can be reduced by population-based screening programs, as has been demonstrated in several large randomised controlled trials of faecal occult blood testing (FOBT).2 The Bowel Cancer Screening Pilot Program currently under way in Queensland, South Australia and Victoria is assessing the practical application of FOBT. While screening of asymptomatic, average-risk individuals for colorectal cancer is advocated by many authorities worldwide (including the National Health and Medical Research Council [NHMRC] in Australia1), uncertainty remains as to the screening test of choice. The numerous publications on the subject are indeed like jigsaw pieces waiting to be put together to reveal the complete picture. In addition to FOBT, the NHMRC-recommended screening options for asymptomatic, average-risk individuals include flexible sigmoidoscopy (FS), and it is timely to review its role here. Colonoscopic studies on asymptomatic people show that 60% of adenomas and cancers occur in the distal colon and are potentially detectable by sigmoidoscopy. Case–control studies have shown that sigmoidoscopy can reduce the risk of subsequent fatal distal colorectal cancer by up to 60%, translating to an approximate 30% reduction in overall colon cancer mortality.3 Direct evidence of the magnitude of benefit from randomised controlled trials that are currently under way is awaited. A 5-yearly screening interval is recommended, based on data from these ongoing studies (which suggest that benefit from sigmoidoscopy extends up to 10 years) and on studies of repeat colonoscopy (which show that significant neoplasia is very uncommon 5 years after polypectomy or a normal examination). What are the performance characteristics of FS? The procedure is typically done in an unsedated patient after administration of an enema and takes 5–10 minutes to perform. At our institution, generally eight procedures are done by one operator over 2 hours. The instrument is advanced as far as is tolerated with reasonable comfort (mean insertion depth, 60 cm; range, 30–110 cm4) with biopsy or removal of polyps performed at the time. The finding of any adenomatous polyp or other suspicious lesion prompts further evaluation with colonoscopy. Fifteen percent of such screenings result in referral for colonoscopy.5 However, some have suggested that diminutive adenomas may not require follow-up — a policy that might reduce colonoscopy referrals to 5% of screenings.6 FS is a safe procedure, with a reported colonic perforation rate of about 1 in 50 000.7 Outpatient colonoscopy, which includes therapeutic procedures, has a perforation rate of about 1 in 1000.8 Concerns are commonly raised about the potential miss rate of FS for lesions in the proximal colon beyond the reach of the instrument and of small lesions that are overlooked in the areas examined. Many heterogeneous studies have addressed the issues of missed proximal colonic lesions and of what distal colonic findings should trigger colonoscopic follow-up. The likelihood of a proximal advanced polyp (ie, one with pathological features that increase malignant potential, such as size or villous architecture) increases with a more advanced distal finding. In the absence of any distal adenoma, 2%–5% of asymptomatic people screened will have isolated proximal advanced lesions.9 Whether this is acceptable in the context of cancer screening may become clear from prospective studies. The fact that sigmoidoscopy may also miss lesions within the area of colon that is examined may have implications for the screening intervals used. It has been shown on repeat FS that polyps may be missed in up to 20% of cases,10 while with colonoscopy a 6% miss rate for adenomas larger than 1 cm has been reported.11 Schoen et al12 recently reported a 0.8% advanced adenoma or cancer rate (there were 6 cancers in 9317 repeat examinations) in patients having a repeat examination 3 years after an apparently normal examination; 80% of advanced lesions were in regions thought to have been adequately examined previously, indicating missed or newly evolved lesions. However, other studies have shown that after 5 years the rate of new findings is low enough to consider lengthening the screening interval.5 The technical aspects of FS are sufficiently clear to enable us to define what FS can and cannot do. From the point of view of screening, FS clearly cannot completely exclude the presence of colon cancer in all asymptomatic people. A distinction must be made between screening the general population and testing the individual seeking screening. For the former, obtaining the greatest mortality benefit safely and at an acceptable cost to the nation is the crux of the matter. Recently published data indicate that FS is a cost-effective screening strategy, although colonoscopy and annual FOBT avert a greater number of cancer deaths.13 The results of randomised controlled trials of screening FS and colonoscopy, currently being conducted, will allow us to make a more accurate comparison with the established data regarding FOBT. Participation rates in sigmoidoscopy screening (23% in initial screening and 54% in follow-up screening at our institution) are encouraging given the invasive nature of FS screening.4,5 The ability of Australian gastroenterologists to accommodate increased demand for colonoscopy, whether as a follow-up to FOBT or FS, remains to be seen. Pieces of the jigsaw continue to fall into place, although it is likely to be some years before a clearly superior screening modality is determined. The emergence of new technologies such as virtual colonoscopy14 and faecal genetic testing will continue to add to the available armamentarium.

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

Coeliac disease (CD) is caused by a complex immunological response provoked by grain protein in susceptible people. The majority of people with CD are symptom-free adults; the remainder are prone to a bewildering variety of signs and symptoms, ranging from infertility to type 1 diabetes. Many patients with undiagnosed CD spend years seeking help for complaints such as chronic tiredness or mild abdominal symptoms. In primary care, an appropriate target group to test for CD is people with anaemia (especially women), chronic tiredness, non-specific abdominal symptoms (including so-called “irritable bowel syndrome”), or a family history of CD. The response to an appropriate gluten-free diet is often life-transforming for symptomatic patients. Positive serological tests for CD require confirmation by duodenal biopsy and, if confirmed, referral to a dietitian and a coeliac society, followed by a life-long gluten-free diet.

John M Duggan MD, FRACP, FRCP

A nasogastric feeding tube became acutely blocked in a young woman with anorexia nervosa. The ward staff tried unsuccessfully to remove the tube, and the patient complained of left cheek and nose pain. The knotted tube had impacted in the nose and was subsequently removed under anaesthesia. Whether the knotting was with fingers or tongue is unknown.

Desmond Wee MB BS · Jon P Clarke MBChB, FANZCA

Can chemoprevention reduce the risk of progression to malignancy? Once a rare tumour, adenocarcinoma of the oesophagus has tripled in incidence in Australia over the past 20 years (Ian McDermid, Australian Institute of Health and Welfare, personal communication). This increase, together with the dismal 5-year survival of patients with this cancer, has focused attention on its risk factors. The strongest of these are symptomatic gastro-oesophageal reflux disease and Barrett’s oesophagus, a condition in which the squamous lining of the lower oesophagus is replaced by metaplastic columnar epithelium. Based on postmortem studies, Barrett’s oesophagus probably affects about 1% of the population in the United States and, at endoscopy, one in five to 10 patients with gastro-oesophageal reflux.1 Evidence of Barrett’s oesophagus (or at least intestinal metaplasia) is commonly found in resection specimens for oesophageal cancer.1 When Barrett’s oesophagus is found at endoscopy, the appropriateness of the patient entering a surveillance program may be considered, with the aim of reducing the risk of death from oesophageal adenocarcinoma. These programs involve regular endoscopy with multiple biopsies from the metaplastic epithelium and interpretation by a skilled pathologist. The rate at which malignancy develops in patients undergoing surveillance has been overestimated in the past because of publication bias; a reasonable estimate appears to be about 1 tumour in 200 patient-years of surveillance.2 The absolute lifetime risk of an individual with Barrett’s oesophagus developing oesophageal adenocarcinoma is probably about 1 in 20, which is comparable to the community risk for developing colorectal cancer. The average age for developing oesophageal adenocarcinoma is the mid to late 60s, but only a few patients with Barrett’s oesophagus die of oesophageal cancer, as comorbidities are common.3 Given these facts, and the problem of ensuring compliance with surveillance, it is not surprising that it has been difficult to demonstrate that surveillance programs reduce mortality, either overall or from oesophageal cancer. The only positive evidence that surveillance improves outcomes derives from the results of surgery on patients with surveillance-detected tumours. These patients generally fare better than those who are diagnosed after presenting with symptoms. Although individual patients may benefit from surveillance, the overall community benefit and cost-effectiveness of these programs is still debated (particularly for programs not conducted in well organised centres by enthusiasts with access to specialist pathologists).4 The use of biomarkers, such as aneuploidy or molecular markers, may help predict the risk of malignancy and may be useful in targeting surveillance programs.5 If surveillance of patients with Barrett’s oesophagus is unrewarding, are there ways to retard the neoplastic process? Recently, the pathobiology of Barrett’s oesophagus has come under intense scrutiny, and it is likely that repeated exposure of the lower oesophagus to reflux of acid and bile is a major factor resulting in metaplasia and subsequent dysplasia.6 Molecular changes in the pathway to malignancy have been identified, including upregulation of cyclo-oxygenase-2 (COX-2).7 The study reported by Hillman and colleagues in this issue of the Journal (page 387) examines the effect of acid suppression on the development of dysplasia in Barrett’s oesophagus.8 The authors analysed the pathology findings from a group of patients enrolled in a surveillance program over the period of time during which proton-pump inhibitors (PPIs) were introduced. The rates of development of dysplasia and malignancy were examined before and after patients started taking PPIs. Although the results must be interpreted in the light of the lack of randomisation, the time effects, and difficulties in distinguishing low-grade dysplasia from inflammatory atypia (problems which the authors recognised and corrected for as far as possible), the study does demonstrate an effect of acid suppression on the development of dysplasia and malignancy. Over 50% of patients (a somewhat high figure) developed low-grade dysplasia within 3 years while not taking PPIs, but this percentage was reduced by almost two-thirds in patients taking PPIs. Interestingly, the dysplasia-free survival curves diverged after only months, suggesting that the effect was rapid. If acid suppression were efficacious in reducing the risk of malignancy, it would be an attractive chemopreventive option, as: it is the cornerstone of therapy for gastro-oesophageal reflux disease, with which Barrett’s oesophagus is closely associated; powerful acid-suppressant drugs are available; and a reduction in gastric acid exposure leads to a concomitant reduction in bile exposure. Combining acid suppression with COX inhibitors (especially aspirin) has further attractions, as COX inhibition alone may reduce the incidence of oesophageal carcinoma by up to half,9 and some of its risks would be ameliorated by acid suppression. COX inhibitors may have an additional benefit on cardiovascular risk in this group of patients. Studies to investigate these issues are under way. So how will this information help us control oesophageal adenocarcinoma? In particular, if acid suppression does reduce the rate of progression of Barrett’s oesophagus to low-grade dysplasia, will this translate into a reduction in the incidence of oesophageal adenocarcinoma? The natural history of low-grade dysplasia is not well defined, while even that of high-grade dysplasia has been debated,10 with the estimated cumulative incidence of cancer varying dramatically between studies, from 56% at 3 years to only 9% at 5 years. The most efficacious method of preventing gastro-oesophageal reflux is good antireflux surgery, so, if control of acid and bile reflux alone were the answer, one might expect to see a dramatic reduction in the rate of oesophageal adenocarcinoma after fundoplication. Unfortunately, this has not been the case.11 One might also predict that the increasing use of proton-pump inhibitors in the past decade, and particularly in the past few years, would reduce the rate of oesophageal adenocarcinoma. However, this effect is not yet evident either in follow-up of patients prescribed omeprazole,12 or in national cancer monitoring (Ian McDermid, Australian Institute of Health and Welfare, personal communication). Even if chemoprevention using potent acid suppression, with or without COX inhibition, can be shown to slow development of malignancy, given the modest absolute risks (1 per 20 patients with Barrett’s oesophagus and perhaps 1 per 200 of those with gastro-oesophageal reflux), we must still identify and target appropriate groups for this or other interventions. We must also carefully examine strategies for efficacy and cost effectiveness. Low-risk strategies, such as chemoprevention, may be broadly applicable, whereas intensive strategies, such as endoscopic surveillance with examination of biopsy specimens for biomarkers of malignancy, will need to be targeted to high-risk groups.13 The jury is still out.

Geoffrey S Hebbard PhD, FRACP · Sanjay Nandurkar FRACP

Objective: To examine whether proton-pump inhibitor (PPI) therapy influences the incidence and progression of dysplasia in patients with Barrett’s oesophagus.Design and setting: Review of prospective data on patients undergoing surveillance with regular endoscopy and biopsy at a private endoscopy centre in Canberra, ACT, between 1981 and 2001.Patients: 350 patients diagnosed with Barrett’s oesophagus.Interventions: PPI therapy was progressively introduced into clinical practice from late 1989. Once begun, PPI therapy was ongoing, with no attempt to reduce the dose.Main outcome measures: Relationship between development of dysplasia or adenocarcinoma and delay between diagnosis with Barrett’s oesophagus and starting PPI therapy was determined by Cox regression analyses, stratified by year of enrolment. Age, sex, presence of macroscopic markers (severe oesophagitis, nodularity, Barrett’s ulcer, stricture) and use of aspirin or non-steroidal anti-inflammatory drugs were considered as confounding factors in the regression analyses.Results: The 350 patients had 1422 surveillance endoscopies, with a median follow-up of 4.7 years. Patients who delayed using a PPI for 2 years or more after diagnosis with Barrett’s oesophagus had 5.6 times (95% CI, 2.0–15.7) the risk of developing low-grade dysplasia at any given time as those who used a PPI in the first year. Similar results were found for the risk of developing high-grade dysplasia or adenocarcinoma (hazard ratio, 20.9; 95% CI, 2.8–158).Conclusions: Use of ongoing PPI therapy appeared beneficial in the prevention of dysplasia and adenocarcinoma in patients with Barrett’s oesophagus. We suggest that all patients with this condition, even those with no oesophagitis or symptoms, should be encouraged to continue long term PPI therapy.

Lybus C Hillman MD, FRACP · Louise Chiragakis MA · Graham L Kaye FRACP · Anthony C Clarke FRCP, FRACP · Bruce Shadbolt PhD

Gautam Ramnath,* Peter Bampton† * Gastroenterology Registrar, † Head of Endoscopy, Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042. peter.bamptonATflinders.edu.au To the Editor: Reflux oesophagitis is an increasingly common medical condition, and up to 10% of all patients with reflux oesophagitis have associated columnar-lined oesophagus, or Barrett’s oesophagus (Box 1).1 This is associated with an increased risk of adenocarcinoma in Australian data of 1 in 176 patient-years.2 Current surveillance guidelines for Barrett’s oesophagus recommend second-yearly endoscopy with quadrantic biopsies at 2–3 cm,3,4 although recent reviews have suggested that the time interval can be extended.1 No prospective study has demonstrated that screening for Barrett’s oesophagus improves survival in the screened population. All the evidence is based on retrospective reviews. If, however, screening is to be of benefit, then adequate tissue sampling is required, otherwise the screening test provides false reassurance and is a poor use of endoscopy resources. We retrospectively audited the endoscopies performed for Barrett’s oesophagus (with intestinal metaplasia) surveillance at our institution over 5 years (1996–2001). In this period, 253 endoscopies were performed as surveillance procedures for Barrett’s oesophagus. We reviewed the endoscopy and histopathology reports to determine whether an adequate number of biopsies had been taken. We found that quadrantic biopsies (defined as four biopsies per 2 cm or less) at every 2–3 cm were performed in 27 of 72 (38%) short-segment, 27 of 150 (25%) long-segment (3–10 cm), and 1 of 13 (8%) extensive (> 10 cm) Barrett’s oesophagus. An acceptable number of biopsies were taken from 40% of patients. The number of biopsies taken per centimetre of Barrett’s oesophagus was inversely proportional to the length of Barrett’s oesophagus. The median interval between surveillance procedures was 12 months. In most surveillance procedures (137/217; 63%) the endoscopy was performed following medical review in the outpatient department rather than because of planned call-back, although in only a few cases did it appear to be due to alarm symptoms such as dysphagia or weight loss. There was little consistency in recommendations among the medical staff. Only one cancer was identified through surveillance in this period, with another presenting in a patient previously on the call-back system who had been lost to follow-up. Three high-grade dysplasias were found. Our retrospective audit revealed that the endoscopists were not following biopsy guidelines, and revealed significant variances in practice. Previously, we found a similar picture with post-polypectomy surveillance; with re-education and development of a prospective review of all cases, we have been able to greatly improve this aspect of practice.5 We were surprised at the result of our audit, and invite other endoscopy units to perform a similar audit of their own practice. It has encouraged us to develop a process similar to the one we have adopted to improve post-polypectomy surveillance. This should improve our practice and enable more efficient utilisation of the endoscopy facility. 1: Barrett’s oesophagus

Gautam Ramnath · Peter Bampton

Even for a simple genetic condition, screening the general population is not straightforward Hereditary haemochromatosis has been touted as the “poster child” for public health genetics. Most cases of haemochromatosis are due to homozygosity for a single mutation leading to iron overload. It is considered to be an ideal candidate for population genetic screening because genetic susceptibility is common, testing is inexpensive, and iron studies can detect early stages of disease. Most importantly, venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload, which include severe fatigue, arthritis, impotence, cirrhosis, diabetes, and cardiomyopathy. However, even though most cases of haemochromatosis are due to a single mutation, it is still unclear how many people homozygous for this mutation will develop serious disease. Consequently, there is uncertainty as to the benefit of screening. Following characterisation of the HFE gene in 1996,1 genetic testing for hereditary haemochromatosis has become available. In Australia, Medicare claims for testing for genetic susceptibility to hereditary haemochromatosis have risen from 14 414 in 1999 to almost 30 000 in 2002.2 It is predicted that about one in 200 Australians are homozygous for the C282Y mutation, which accounts for about 90% of cases of hereditary haemochromatosis identified to date in high-risk families.3 A person carrying two copies of the C282Y mutation is at risk of developing iron overload and subsequent disease. However, like all diseases, haemochromatosis is defined by pathology, and a person does not have hereditary haemochromatosis unless body iron stores, as reflected by abnormal iron indices (serum ferritin and fasting transferrin saturation), are elevated. There is a wide spectrum of potential consequences of iron overload, and while about 60% of C282Y homozygotes will eventually develop iron overload,3,4 it is not known what proportion will progress to serious clinical disease. The answer is complicated by the long latency for development of disease (probably many years) and the possible modifying effects of sex, diet, environment and other genes. Recent population-based studies have shed light on disease expression in people genetically susceptible to hereditary haemochromatosis. In the Busselton study, 16 homozygotes were identified from a sample of 3011 adults (1 in 188) with a median age of 52.7 years (range, 20–79 years).3 Twelve were not previously aware of their genetic risk, and of these, seven had elevated serum ferritin levels and the four with normal iron studies were premenopausal women. Half of the original 16 had clinical features consistent with hereditary haemochromatosis, although the prevalence of symptoms in non-homozygotes of the same age was not presented for comparison.3 A recent study in California identified 152 homozygotes from a sample of 41 038 individuals (1 in 270) with mean age 57 years (SD, 14).4 Among these homozygotes, 76% of men and 54% of women had raised serum ferritin levels. Homozygotes were twice as likely as controls to report liver problems (8.1% versus 4.1%), but there was no evidence for a higher prevalence in homozygotes for any other symptom associated with hereditary haemochromatosis. The authors estimated only a small percentage of homozygotes would develop frank clinical haemochromatosis.4 However, exclusion of people with pre-existing disease may have biased this estimate downwards.5 Although it is possible that disease expression is greater in Australia, owing to our relatively higher meat and alcohol intake,6 the results of the Californian study indicate that further population-based studies are necessary. The key factors in considering population screening of asymptomatic people are whether it will do more benefit than harm and whether it is cost-effective.7 International expert opinion has been cautious about population genetic screening for hereditary haemochromatosis,8,9 given the limited population data and possible adverse effects of screening, such as the potential for insurance discrimination in the United States. In Australia, health insurance is population-rated and discrimination is illegal. For life insurance, an agreement has been reached with the insurance industry that considerably reduces the risk of discrimination.10 Because cost–benefit analyses depend upon the number of people for whom disease can be prevented, enthusiasm for population screening for hereditary haemochromatosis has been dampened by the Californian findings. Even if these results are confirmed in whole or in part, it could be argued that, in Australia, there is minimal “cost” to genetically susceptible individuals in becoming blood donors, which virtually eliminates their risk of disease.11 However, until it can be demonstrated that benefits or savings outweigh any potential harm or costs, population genetic screening programs — paid for by the public purse — are on the backburner. The current standard of care remains cascade screening (ie, testing the HFE mutation status of first-degree relatives of individuals who have developed iron-related disease), because it is reasonable to assume that familial homozygous individuals are more likely to express disease.12 Genetic testing for HFE mutations is also appropriate as a follow-up in people with abnormal iron studies (ie, elevated serum transferrin saturation and serum ferritin). Iron studies should be considered for patients with unexplained symptoms or conditions consistent with hereditary haemochromatosis, such as severe fatigue, liver disease and diabetes, although the predictive value of such testing is likely to be low. C282Y homozygotes found to have high serum ferritin levels, with or without increased transferrin saturation, should have regular therapeutic venesection. Those with normal iron studies should be monitored expectantly, but do not require venesection unless they develop persistent abnormalities in serum ferritin levels. The Human Genome Project has made a great step forward in mapping tens of thousands of genes, but it may be decades before we can predict which individuals are most likely to develop serious disease. Even for a condition as apparently straightforward as hereditary haemochromatosis, the path to general population genetic screening has proven more complicated than initially expected.

Dorota M Gertig MB BS, DSc, FAFPHM · John L Hopper MSc, PhD · Katrina J Allen MB BS, FRACP, PhD

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

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

A 79-year-old man presented with diarrhoea and vomiting but with no abdominal peritoneal signs. He had a raised C-reactive protein level, but other blood test results (including amylase and liver function) and an abdominal radiograph were within normal limits. After conservative treatment failed, the patient underwent colonoscopy, which revealed cobblestone nodularity with ulceration in the terminal ileum, consistent with Crohn’s disease. There was no evidence of large bowel obstruction. A subsequent computed tomography scan revealed concentric circles in the terminal ileum consistent with a gallstone (Box). A diagnosis of gallstone ileus was made and the gallstone was removed with laparoscopic assistance. A fistula between the gallbladder and the duodenum, observed at operation, was left alone. The patient made an uneventful recovery.

Hashim Hashim MB BS, MRCS Surgical · Alec Engledow MB BS, FRCS · Steve Warren MS, FRCSE (Gen Surg) Consultant

Rosie G Scott,* John T Edwards,† Richard M Mendelson,‡ Geoffrey M Forbes§ * Research Fellow, ‡ Radiologist, Department of Diagnostic and Interventional Radiology; † Gastroenterologist, § Gastroenterologist (corresponding author), Department of Gastroenterology and Hepatology; Royal Perth Hospital, PO Box X2213 GPO, Perth, WA 6000 geoff.forbesAThealth.wa.gov.au To the Editor: The burden of colorectal cancer can be minimised, firstly, by early and appropriate investigation of symptoms; secondly, by screening those at higher-than-average risk without symptoms; and thirdly, by community-based screening of asymptomatic people aged over 50 years who are at average risk. Major screening programs using faecal-occult-blood testing (FOBT)1-3 or flexible sigmoidoscopy4 have not necessarily made this differentiation. These tests lack the sensitivity of colonoscopy, which is generally indicated for those with symptoms or a strong family history of colorectal cancer. In our recent community-based screening program in which we used virtual colonoscopy, we excluded those at higher than average risk for colon cancer (that is, they were symptomatic or had at least one first-degree relative with colon cancer), as our standard of care for these patients is colonoscopy. They were given verbal and written advice to see their general practitioner, with the expectation that most should have colonoscopy. They were followed up an average of 12 months (range, 6–15 months) later, by letter and telephone, to determine the outcome of this advice. Of 2000 participants aged 50–69 years who were offered screening, 90 (4.5%) described having symptoms or a first-degree relative with bowel cancer, but had not undergone investigation. Follow-up information obtained from 71 of these people indicated that 21 had a relevant family history and 50 described recent bowel symptoms. Only 35 (49%) had discussed further investigations with their GPs — 19 (27%) had undergone colonoscopy, and five of these (26%) had advanced colorectal neoplasia (CRN). One had tubular adenoma (> 1 cm), one showed villous architecture, one had intramucosal carcinoma, and two had cancer. Four other participants had had negative results on other investigations. These were FOBT alone in three (two symptomatic, one with family history) and barium enema in one who had bleeding. Common reasons for not consulting their GPs were because of good health (15 participants), resolution of symptoms (12), and perceived lack of need for tests (10). These data have important implications for CRN screening programs, including recently commenced Australian pilot programs (www.cancerscreening.gov.au). Firstly, there is likely to be an improved yield of advanced CRN when a previously uninvestigated high-risk group is identified within a screening program. Secondly, people identified as having higher-than-average risk for CRN need special attention to ensure there is adherence to advice on appropriate follow-up. Thirdly, procedures are required to ensure colonoscopy is appropriately undertaken when participants do consult their GPs. Accordingly, rather than adopting an exclusion policy within a screening program based on FOBT or flexible sigmoidoscopy, we believe it is appropriate that people at greater risk for CRN are identified and offered colonoscopy within that program.

Rosie G Scott · John T Edwards · Richard M Mendelson · Geoffrey M Forbes