Digestive system diseases

To the Editor: The recent case report by Chow and colleagues raises questions about the causal link between black cohosh use and hepatotoxicity.1 The authors state that the patient had no history of “significant alcohol consumption”, but a presumably related adverse drug reaction report available from the Therapeutic Goods Administration reveals her alcohol use was “3–4 units [of] alcohol per day, [with] 1–2 alcohol-free days per week”.2 Alcohol misuse is a known risk factor for severe liver disease, as is gastric bypass surgery for obesity,3 also in the patient’s history. Unfortunately, because histological examination of the liver 6 weeks after first presentation found no recognisable residual hepatocytes, the diagnoses of alcoholic steatohepatitis, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis cannot be excluded. Without this, the specific conclusion of the liver biopsy that the “Massive hepatocellular necrosis [was] associated with herbal medication”2 cannot be substantiated. The patient “was not taking any other medications, including other herbal preparations”, but the use of multivitamins was disclosed,2 without further information on ingredients, indication, dosage and duration of use. Notably, an overdose of vitamin A can cause severe liver disease. Finally, discontinuation of black cohosh failed to reduce the patient’s bilirubin levels, suggesting ongoing liver cell destruction by the as-yet unknown agent. Chow et al state “Extensive investigations to exclude other causes of acute liver failure gave negative results”.1 It is unclear whether rare liver diseases were excluded, notably herpes infection, which has been reported to cause severe herpetic hepatitis. Nor was polymerase chain reaction testing performed for hepatitis viruses. The authors mentioned other published case reports of hepatotoxicity potentially linked with black cohosh.1 A recent assessment of 42 cases by the European Medicines Agency (EMEA) concluded that most were insufficiently documented, or were otherwise inappropriate for analysis.4 A case in the United States initially described as “probable” (> 1000% of the recommended dosage of black cohosh), based on the report that the patient “did not drink alcohol or use illicit drugs and was not taking any medications”, was later corrected.5 The patient testified under oath that she drank wine regularly and used other drugs, and a US court judged there was no evidence to establish that black cohosh had caused her liver disease.6 There is no apparent credible evidence that black cohosh caused liver failure in the patient described by Chow et al.1 A daily alcohol consumption of 30–40 g should be considered principally in any causality assessment. In addition, idiopathic reasons, rare or unclear liver diseases, and other medications should be considered as possible causes. Even in patients with liver disease who consume little or no alcohol and have no exposure to other toxic agents, the cause of the disease remains unclear in up to 30%. In view of this, reliable and sufficient reporting of adverse drug reactions is a necessary precondition to any reliable assessment of causality.7

Belal Naser · Eckehard Liske

To the Editor: The case reported by Chow and colleagues of liver failure associated with the use of black cohosh1 requires comment regarding causality. The case has also been the subject of an adverse drug reaction report by the Therapeutic Goods Administration (TGA), and a possible causality has been proposed.2 At presentation on 23 May 2006, the patient was aged 50 years (TGA),2 not 51 as stated by Chow et al.1 Her bodyweight was 88 kg (TGA)2 after gastric bypass for obesity.1 She had been taking black cohosh (20 mg daily) intermittently for 3 years. The subsequent temporal course is essential for assessing causality. According to the TGA report,2 the patient increased the dose of black cohosh to 40 mg daily on 31 March 2006 and stopped taking it on 31 May 2006. The case report describes a 2-month history of lethargy, nausea and arthralgia,1 obviously reported at first presentation. Back calculation shows symptom onset around 23 March 2006. Thus, symptoms emerged 1 week before the dose increase, suggesting a lack of temporal, and hence causal, association. The patient had several risk factors for severe liver disease.1 Risky use of alcohol for women is defined as more than seven standard drinks per week or more than three drinks on a single occasion.3 The patient had a daily intake of 3–4 units of alcohol, with 1–2 alcohol free days per week (reported by the TGA),2 rendering her at some risk of alcoholic liver disease. Moreover, gastric bypass with partial resection reduces gastric mucosal alcohol dehydrogenase and consequent gastric ethanol metabolism. In combination with rapid gastric passage of alcohol into the jejunum, this leads to high blood ethanol concentrations, another risk factor for liver disease. Risk factors for possible non-alcoholic steatohepatitis and cirrhosis are obesity and gastric bypass. Other causes were not excluded, including Wilson’s disease (by 24 h urinary copper measurement), hepatitis E, herpetic liver disease and infection by varicella zoster virus, parvovirus B19, parainfluenza virus, adenovirus and cytomegalovirus (by assessing for a change in IgG titre after disappearance of IgM). The marked hepatic mononuclear infiltrate is compatible with some viral infections. Certainly, various herbal products may cause liver disease. A good example is kava,4 but not black cohosh.5,6 The European Medicines Agency examined 42 cases of liver disease with a suspected association with black cohosh, and found that only four patients had some grades of causality.5 Reassessment showed that two of these patients had herpetic hepatitis, one had autoimmune hepatitis, and the fourth was not assessable.6 Further studies are necessary to show clearly whether black cohosh is potentially hepatotoxic.

Rolf Teschke

In reply: Teschke questions the temporal sequence in our reported case1 by raising an ambiguity in dates. We wish to clarify: when the patient first presented on 23 May 2006, lethargy, arthralgia and nausea had been present for only about 3 weeks. This was well after the dose increase in black cohosh in March 2006. As such, the dose escalation definitely preceded the patient’s symptoms and liver failure. To further explore causality would require rechallenge with black cohosh, which we consider dangerous and unethical. Other unlikely causes of liver failure raised by Teschke, although theoretically possible, were not evident. The clinical course and histological findings in the pretransplant biopsy and explanted liver categorically excluded alcoholic cirrhosis and non-alcoholic steatohepatitis as causes of the liver failure. We also reiterate that there was no previous history of liver disease or other medication use. Increasing numbers of case reports are being published showing evidence of hepatotoxicity in patients taking black cohosh. Two well documented cases of seriously deranged liver function in patients taking black cohosh, which resolved on ceasing its use, have just been reported.2 Teschke concedes that four other cases have been reported where some causality between black cohosh and hepatotoxicity was evident.3 Neither Teschke nor Naser and Liske offer any reassurance on the long-term safety or lack of toxicity of black cohosh by referencing any properly conducted safety study. Certainly, there is recent in-vitro and in-vivo evidence in a rat model that black cohosh is toxic to hepatocyte mitochondria and impairs oxidative phosphorylation, resulting in apoptotic hepatocyte death.4 It is notable that, based on available evidence, the Australian Therapeutic Goods Administration requires preparations containing black cohosh to carry a warning of potential liver toxicity, stating that “there appears to be an association between the use of black cohosh and liver damage, but that it is very rare”.5 Furthermore, in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency stated, “Warnings regarding rare adverse reactions in the liver should be added to the product information for black cohosh for both licensed and unlicensed products”.6 Government authorities in Europe3 and Canada7 have raised similar concerns. Long-term studies as well as further animal studies would be welcome in this area.

Elizabeth C-Y Chow · Marcus Teo · John A Ring · John W Chen

Objective: To determine the prevalence and associated epidemiological features of Helicobacter pylori infection in child refugees in Western Australia.Design and participants: Cross-sectional study of 193 eligible African refugee children (aged < 16 years) at their initial health assessment after resettlement in Australia between 1 February and 30 November 2006.Main outcome measures: (i) Prevalence of H. pylori infection determined by monoclonal faecal antigen enzyme immunoassay testing (MFAT); (ii) associations of H. pylori infection with epidemiological factors (age, sex, transit through refugee camps, comorbidities and treatment interventions).Results: MFAT was performed in 182 of the 193 children; 149 of these 182 (82%) had H. pylori infection. Age was an independent predictor of H. pylori infection (odds ratio [OR], 1.18; 95% CI, 1.07–1.31). No sex differences were observed. Premigration antimalarial therapy (with sulfadoxine–pyrimethamine and artesunate) significantly reduced the prevalence of H. pylori infection (age-adjusted OR, 0.33; 95% CI, 0.15–0.75).Conclusion: African refugee children have a high prevalence of H. pylori infection. Increasing age is a strong predictor of infection and antimalarial treatment may have a protective effect.

Sarah Cherian MB BS(Hons), FRACP · David Forbes MB BS, FRACP · Frank Sanfilippo BPharm, PhD · Angus Cook MB ChB, PhD · David Burgner MB ChB, FRACP, PhD

Tumour necrosis factor inhibitors have revolutionised the management of Crohn’s disease, but reports of a possible association between concomitant infliximab and immunomodulator therapy and hepatosplenic T-cell lymphoma (a rare form of aggressive non-Hodgkin’s lymphoma) have emerged. We describe the first case in Australia of hepatosplenic T-cell lymphoma in a patient who had been treated with infliximab and immunomodulators for Crohn’s disease. Clinical recordIn January 2006, a 39-year-old man of European background presented with severe sepsis of unidentified source. This was complicated by hypotension and multiorgan failure, including renal impairment, abnormal liver function and myocardial injury, and he required intensive care. He had a 13-year history of active perianal and ileal Crohn’s disease, which had been treated with prednisolone (varying doses) continuously from 1993, and with azathioprine (2–2.5 mg/kg) from 1993 to 1994 and then continuously from August 1999 (after drainage of a perianal abscess). He had also received three doses of infliximab (5 mg/kg) between November 1999 and January 2000, which achieved a partial response. Azathioprine and prednisolone therapy were continued after infliximab therapy, with relatively good control of symptoms. Results of full blood examinations during azathioprine therapy were within normal ranges. On admission, azathioprine therapy was discontinued, but corticosteroids were continued. Blood cultures grew methicillin-sensitive Staphylococcus aureus. Full blood examination revealed mild anaemia (haemoglobin level, 91 g/L; reference range [RR], 130–170 g/L) and mild lymphocytopenia (white blood cell count, 0.6 × 109/L; RR, 4.0–11.0 × 109/L), but other parameters were initially normal. Biochemical analysis revealed acute renal failure (potassium, 6.5 mmol/L [RR, 3.5–5.0 mmol/L]; bicarbonate, 21 mmol/L [RR, 22–31 mmol/L]; creatinine, 580 μmol/L [RR, 60–110 μmol/L]; and urea, 19.9 mmol/L [RR, 2.5–8.3 mmol/L]). Liver function tests revealed transaminitis (alanine aminotransferase, 432 U/L [RR, < 55 U/L]; aspartate aminotransferase, 2246 U/L [RR, < 50 U/L]; and bilirubin, 53 μmol/L [RR, < 19 μmol/L]). There was also evidence of coagulopathy (international normalised ratio [INR], 2.8 [RR, 0.8–1.3]), grossly abnormal levels of inflammatory markers (C-reactive protein, 218 mg/L [RR, < 8 mg/L]; erythrocyte sedimentation rate, 140 mm/h [RR, 2–14 mm/h]), and elevated troponin I levels (5.24 μg/L; RR, < 0.10 μg/L). Nine days after admission, the patient developed pancytopenia (haemoglobin level, 78 g/L; white blood cell count, 0.9 × 109/L; and neutrophil count, 0.3 × 109/L [RR, 2.0–8.0 × 109/L]). This was attributed to drug-induced suppression of bone marrow, and granulocyte-colony stimulating factor (G-CSF) was administered. On discharge, leukocyte and neutrophil levels were normal, G-CSF therapy was discontinued, and follow-up was arranged. Ten days after the patient was discharged, he re-presented with a 2-day history of fever, malaise and non-specific abdominal pain. Physical examination revealed a temperature of 38.5°C, tachycardia (heart rate, 110 beats/min), and hypotension (blood pressure, 100/60 mmHg); cardiovascular and respiratory systems were otherwise unremarkable. Abdominal examination revealed new hepatosplenomegaly, with no stigmata of chronic liver disease. There was no clinical evidence of lymphadenopathy. Repeat haematological testing revealed pancytopenia: haemoglobin level, 100 g/L; white blood cell count, 0.7 × 109/L; platelet count, 48 × 109/L (RR, 140–400 × 109/L); neutrophil count, 0.0 × 109/L; and lymphocyte count, 0.5 × 109/L (RR, 1.2–4.0 × 109/L). A blood film showed atypical lymphocytes and blast cells. Serum lactate dehydrogenase level was grossly elevated at 5351 U/L (RR, 210–420 U/L), and liver function tests showed abnormal results. Abdominal computed tomography confirmed gross splenomegaly, with the spleen being 24 cm long on its major axis, but no lymphadenopathy. Microscopic examination of a liver core biopsy specimen revealed an atypical lymphoid infiltrate in the sinusoids, especially around central veins (Box), with immunophenotype bcl-2+, CD3+, CD43+, Ki67+, ALK1 −, bcl-6 − , CD5 −, CD10 −, CD20 −, CD30 −, CD79 − and cyclin D1 − . Subsequent genetic studies of a bone marrow biopsy specimen revealed rearrangement of the T-cell receptor γ-chain gene, consistent with hepatosplenic T-cell lymphoma (HSTCL). The lymphoma was treated with one cycle of cyclophosphamide, mesna, dexamethasone, doxorubicin and vincristine, which achieved a partial response, but subsequent salvage chemotherapy with ifosfamide, carboplatin and etoposide did not arrest disease progression. In June 2006, the patient received a sibling allogeneic bone marrow transplant, after conditioning with etoposide and total body irradiation.1 The patient remained largely free of disease after transplantation, with monitoring on an outpatient basis and adjustment of immunosuppression as clinically indicated. However, in April 2007, he was hospitalised for investigation of diarrhoea and worsening liver function. He underwent colonoscopy and biopsy of a caecal polypoid mass; results of histological examination were consistent with recrudescence of HSTCL. Positron emission tomography showed multiple sites of relapse. A palliative approach was adopted, and the patient died in June 2007. DiscussionWe describe the first case, to our knowledge, in Australia of HSTCL in a patient with Crohn’s disease who had been treated with infliximab and immunomodulators. Inhibitors of tumour necrosis factor (TNF) such as infliximab have shown great efficacy in the treatment of luminal and fistulising Crohn’s disease, as well as ulcerative colitis.2 Infliximab is a chimeric (human/murine) monoclonal antibody that binds to human TNF-α. It was approved by the United States Food and Drug Administration (FDA) in 1998 for the treatment of moderate-to-severe Crohn’s disease when response to immunomodulator therapy is inadequate. More recently, the FDA has expanded the indication to include ulcerative colitis refractory to conventional treatment. In Australia, the Pharmaceutical Benefits Advisory Committee recently approved TNF inhibitors for the treatment of Crohn’s disease. However, the safety of such biological therapy is a concern: a recent meta-analysis reported a threefold increase in the risk of malignancy (solid and haematological) with the use of anti-TNF therapy in rheumatoid arthritis patients.3 This increase may be partly due to severity of disease or to other aspects of disease management. Interestingly, to date there have been no reports of HSTCL in rheumatoid arthritis patients. The TREAT (Crohn’s Therapy Resource, Evaluation and Assessment Tool) registry, which monitors over 3000 patients with Crohn’s disease who have been treated with infliximab, has not reported an increased incidence of lymphoma.4 However, it is estimated that a substantially larger number of patients would need to be monitored to detect a significant increase in a rare adverse event, such as lymphoma.5 Between 2000 and 2006, the Adverse Drug Reactions Advisory Committee received 319 reports involving anti-TNF therapy, including five cases of lymphoma.6 HSTCL is a rare form of aggressive non-Hodgkin’s lymphoma that comprises 5% of peripheral T-cell lymphomas. Reports of approximately 120 cases have been published worldwide. Eight cases of HSTCL have been identified from the post-marketing infliximab safety database run by the FDA, which seems more than expected, all in young men with a history of Crohn’s disease and concomitant use of azathioprine or mercaptopurine.7 In addition, there have been 15 reports of ‘‘T-cell lymphoma’’ in patients treated with infliximab, but data from the Adverse Event Reporting System were limited.7 Furthermore, there have been no reports of HSTCL associated with other anti-TNF therapies (eg, etanercept and adalimumab) used for any indication.7 Of note, there have been four reports of HSTCL in patients who received azathioprine or mercaptopurine alone for 4–6 years.8 The case we describe differs substantially from previously reported cases of HSTCL associated with concomitant infliximab and immunomodulator treatment in Crohn’s disease. To our knowledge, it involves the oldest patient and longest lead time (72 months) reported to date. Patients in most other cases have been younger than 22 years, with a lead time of less than 58 months7 (unpublished data, Centocor, Horsham, Pa, USA). Recent data suggest an association between lymphoma — especially HSTCL — and concomitant use of infliximab and immunomodulators in Crohn’s disease. However, the mechanism of this possible association remains unclear. The use of biological therapy as a “bridge” to stabilise the disease, while waiting for immunomodulators to become clinically effective, may need to be considered with increased caution. Immunomodulators might need to be avoided after infliximab therapy, and alternative treatments considered. These may include maintenance with ongoing biological therapy alone, use of newer anti-TNF therapy, or earlier surgery (especially in young men). Until further evidence emerges, long-term surveillance of patients who have used biological therapy is warranted. In particular, biological therapy should be used cautiously in the management of refractory inflammatory bowel disease. The decision to use infliximab should be tempered by observations of an association with HSTCL, and strategies for long-term maintenance therapy need to be developed. Liver core biopsy specimen of a patient with Crohn’s disease, following infliximab and immunomodulator therapy Low magnification (A: haematoxylin and eosin stain; original magnification, × 10) and high magnification (B: CD3 stain; original magnification, × 40) views of a liver core biopsy specimen, showing prominent atypical lymphoid infiltrate in the sinusoids and around central veins, and occasional red cell extravasation. The high magnification shows strong CD3 staining (arrows), findings consistent with hepatosplenic T-cell lymphoma.

Musa Drini MB BS · Peter J Prichard MD, FRACP · Gregor J E Brown PhD, FRACP · Finlay A Macrae MD, FRACP, FRCP

A 51-year-old woman presented with a 2-day history of left iliac fossa pain. Axial and coronal computed tomography images (Figures) revealed a linear intraluminal foreign body (arrows) impacted in the wall of a blind-ended loop of small bowel over the midline, consistent with a fishbone in a Meckel diverticulum. Small bowel dilatation due to ileus (D) and inflammatory stranding in the peritoneal fat (S) were also present. Surgery revealed pinpoint bowel perforation caused by a 2 cm long fishbone, from Pampus argenteus (silver pomfret), in a 5 cm long Meckel diverticulum.

Now that we can predict risk accurately, we need to reconsider screening strategies The recent completion of the Human Genome Project offered great promise that medical genetics would have a population-based impact on the prevention and treatment of inherited conditions. A common inherited condition, hereditary haemochromatosis, was initially touted as a “poster child” for population genetic screening. Most cases are due to homozygosity for a single mutation of the HFE gene, leading to iron overload. Hereditary haemochromatosis is considered an ideal candidate for population genetic screening as genetic susceptibility is common, testing is inexpensive, and iron studies can detect early stages of the disease.1 Most importantly, venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload,2 which include severe fatigue, arthritis, impotence, cirrhosis, diabetes, and cardiomyopathy.3 However, even for an inherited condition as apparently straightforward as haemochromatosis, justifying population genetic screening has proven more complicated than initially expected.4 After the gene linked with hereditary haemochromatosis was identified in 1996,5 a flurry of publications called for the consideration of population genetic screening, as it was thought that most people who were homozygous for the C282Y mutation would eventually develop the disease. Although more than 90% of cases are due to C282Y homozygosity,3 there is now good evidence that not all those who are homozygous will progress through all stages of the disease. These stages comprise genetic predisposition without abnormality; iron overload (raised serum ferritin in the presence of a raised fasting transferrin saturation) without symptoms; iron overload with haemochromatosis-associated symptoms, such as arthritis and fatigue; and iron overload with organ damage, particularly cirrhosis.6 Although most of those who are homozygous appear to develop raised serum ferritin and raised transferrin saturation by the fifth decade of life,7 until now there have been few reliable data on the number of homozygous individuals who develop disease as a result of iron overload. Population estimates of the prevalence of non-specific signs and symptoms of haemochromatosis (eg, arthritis and fatigue) and disease due to documented iron overload (eg, cirrhosis) in C282Y homozygous individuals have been hindered by either the failure to clinically assess individuals before knowledge of their genetic status or an inability to account for the long lead time of preclinical iron-overload status. A cross-sectional population study of participants aged 20–80 years suggested that disease attributable to haemochromatosis occurs in fewer than 1% of those who are homozygous, regardless of sex.8 However, this study did not conduct clinical examinations or liver biopsies, and a quarter of the homozygous patients were excluded on the basis that they had been previously diagnosed. This exclusion would be expected to reduce the estimate of clinical penetrance of C282Y homozygosity. Furthermore, the study included homozygous patients of ages at which disease would not be expected to have developed. Until recently, there had been only two longitudinal studies of hereditary haemochromatosis designed to accurately estimate the proportion of homozygous patients who will develop disease secondary to iron overload.9,10 However, with a combined total of 23 patients, they were substantially underpowered to assess disease prevalence. In the largest longitudinal prospective study to date, my colleagues and I assessed 203 homozygous individuals among a healthy population of 31 192, followed up over 12 years.11 Data were collected by physicians who were blinded to genotype, and liver biopsies were performed as clinically indicated (serum ferritin > 1000 μg/L, unexplained hepatomegaly or raised serum aminotransferase levels).12 We found that homozygous individuals with a serum ferritin level higher than 1000 μg/L were at increased risk of haemochromatosis-associated signs and symptoms, when compared with either those who were homozygous with a serum ferritin level of 1000 μg/L or less, or individuals with other HFE genotypes. In particular, homozygous men with a serum ferritin level higher than 1000 μg/L reported greater fatigue, use of arthritis medication and history of liver disease than men without the C282Y mutation. We also assessed the proportion of homozygous individuals with disease that was directly attributable to iron overload using the combined definition of documented iron overload13 and one or more of the following: cirrhosis, liver fibrosis, hepatocellular carcinoma, raised aminotransferase concentration, physician-diagnosed symptomatic hereditary haemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. Iron overload-related disease developed in 28% of homozygous men, but only 1% of homozygous women.11 Our study is important because it enables us, for the first time, to make accurate predictions about the proportion of those at genetic risk of haemochromatosis who will develop symptoms that could otherwise be prevented. Furthermore, we confirmed that homozygous individuals with a serum ferritin level higher than 1000 μg/L were not only at increased risk of cirrhosis, but also of non-specific signs and symptoms of haemochromatosis. This has implications for a cost-effectiveness analysis of population genetic screening for hereditary haemochromatosis. Other criticisms of such screening,14 including concerns over insurance implications and creating a cohort of “worried well” among those at genetic risk of haemochromatosis, have proved unfounded.15,16 It appears that cost is the last barrier to screening. The questions that remain regarding population screening include: Would it be more cost-effective to simply offer screening to men? What is the most cost-effective age to screen at? What is the most pragmatic way to access a population before an age at which disease is likely to develop? Hereditary haemochromotosis may yet offer a prototype for population genetic screening programs, but the journey of justification has offered unexpected challenges.

Katrina J Allen BMedSc, FRACP, PhD

Clinical record A 47-year-old woman — an Australian resident of North Indian origin — was referred to our outpatient clinic. She had a 4-year history of lethargy on a background of primary hypothyroidism that was diagnosed 2 years earlier. She reported weakness, myalgia, poor concentration and chronic diarrhoea, which had been attributed to irritable bowel syndrome after a colonoscopy found no abnormalities. Given her racial origin, coeliac disease had not previously been considered. Rather, a chronic pain syndrome was diagnosed as the cause of the myalgia, and was managed with narcotic analgesia. The patient’s medications also included thyroxine (50 μg daily). Her body mass index was 29.5 kg/m2; normal findings were obtained on physical examination, and she was clinically euthyroid on thyroxine replacement. Hashimoto’s hypothyroidism with under-replacement of thyroxine, secondary hyperparathyroidism with vitamin D deficiency, and impaired fasting glycaemia were biochemically confirmed (Table). A high vitamin B12 level was also noted, and this was attributed to recent intramuscular injection of vitamin B12. Bone density was measured using the Lunar Prodigy DXA system (GE Healthcare, Madison, Wis, USA), which revealed osteopenia with lumbar bone mineral density (BMD) of 1.02 g/cm2 (T-score, − 1.9 SD) and total femoral BMD of 1.02 g/cm2 (T-score, − 1.6 SD). Titration of thyroxine to a weekly dose of 1400 μg and vitamin D3 replacement dosage of 6000 IU daily, over a 6-month period with confirmed compliance, failed to ameliorate hypothyroidism and vitamin D deficiency. In view of her history, previous investigations and progress, serological testing for coeliac disease was carried out. Results were positive for endomysial IgA antibodies, with normal total IgA antibody titre. Also, histological analysis of a small bowel biopsy specimen was consistent with coeliac disease (Figure). A 6-month gluten-free diet resulted in complete resolution of lethargy, diarrhoea and myalgia. Hypothyroidism was corrected with a weekly dose of 750 μg thyroxine, and both secondary hyperparathyroidism and impaired fasting glycaemia resolved (Table). Histological examination of small bowel mucosa Histological examination showed focal, partial villous atrophy and crypt hyperplasia, with evidence of chronic inflammation in the lamina propria (original magnification, × 400) — consistent with coeliac disease. Results of laboratory investigations At presentation After 6 months of gluten-free diet Reference range Thyroid-stimulating hormone (mIU/L) 13.4 8.3 0.3–4.0 Thyroxine, free (pmol/L) 12 15 10–25 Thyroid antimicrosomal antibody titre 25 600 — < 100 Calculated ionised calcium (mmol/L) 1.08 — 1.00–1.25 25-hydroxyvitamin D (nmol/L) < 15 34 40–150 Parathyroid hormone (pmol/L) 6.0 4.5 1.0–5.2 Fasting glucose (mmol/L) 6.3 5.4 < 5.6 Glycated haemoglobin (%) 6.2 5.5 < 6.0 Vitamin B12 (pmol/L) > 1470 — 145–637 Ferritin (μg/L) 124 — 15–200 While the prevalence of coeliac disease in the European population has been estimated to range from 1 in 150 to 1.5 in 1000,1 the prevalence in the Indian population is unknown due to lack of population-based data,2 leading to the common misconception that coeliac disease is rare. However, recent studies using new serological screening methods have demonstrated gross underdiagnosis of coeliac disease in the past,1-3 and an unexpectedly frequent prevalence in countries populated by non-Europeans. The highest reported population prevalence is in the Saharawi people of Arab–Berber origin, who live in the Sahara desert, with a prevalence of 5.6% — almost tenfold higher than that reported from most European countries.4 Similarly, recent studies in India found a prevalence of 9%–26% in patients who presented with chronic diarrhoea or malabsorption.5,6 The pathogenesis of coeliac disease is related to intolerance of gluten that results in a T-lymphocyte-mediated, small intestinal enteropathy in genetically predisposed individuals, who commonly express the HLA-DQ2 or HLA-DQ8 haplotypes.7 Such genetic predisposition is common in Europeans, but also occurs in Indian patients, as evident from detection of the HLA-DQ2 heterodimer in 14 out of 15 North Indian patients with coeliac disease.8 The HLA-DQ2 haplotype is also found in almost 25% of the healthy North Indian population, similar to the Western population,9 which has led to speculation that some Indians share ancestral origin with “ancient Caucasians” from the Fertile Crescent.9,10 Environmental challenge from the increasingly popular Western diet, which is gluten-rich, may also contribute to observed changes in the epidemiology of coeliac disease. For example, “summer diarrhoea” has been described in communities of Punjabis and Gujaratis from India. Traditionally, wheat replaces maize during summer in India, and Punjabis and Gujaratis residing in England and Canada have been reported to develop coeliac disease when exposed to a gluten-rich diet.11,12 Another misconception about coeliac disease patients is that they are all underweight. In one study, the mean body mass index of 371 patients with coeliac disease was 24.6 kg/m2, with only 5% being underweight, while 39% and 13% were in the overweight and obese ranges, respectively.13 Our patient’s body mass index was in the overweight range, which may have contributed to the delay in diagnosis until she was referred to our clinic. Coeliac disease is also associated with a wide range of autoimmune conditions. The presence of Hashimoto’s hypothyroidism was a clue to an autoimmune cluster in our patient, and persistent hypothyroidism despite large replacement doses of thyroxine is highly suggestive of a malabsorption disorder, such as coeliac disease. The complex symptomatology of our patient illustrates the non-specific, extraintestinal manifestations of coeliac disease, including lethargy, neuropsychiatric complaints, and myalgia from vitamin D deficiency; the latter may also lead to impaired insulin secretion and result in impaired fasting glycaemia.14 A high index of suspicion is required to screen for the disease, which is associated with significant morbidity. In conclusion, screening for coeliac disease with serological testing is non-invasive and should be considered in Indian patients with suggestive symptoms or associated autoimmune conditions. It is important for clinicians to overcome historical bias and consider coeliac disease as a diagnosis in non-European patients. Early diagnosis may help to avoid unnecessary investigation and reduce the long-term risk of small bowel malignancies associated with coeliac disease. Compliance with a gluten-free diet not only reduces symptoms, but also rectifies malabsorption of micronutrients and medications, which impact on comorbidity such as, in this case, abnormalities of thyroid replacement and metabolism of bone and glucose. Lessons from practice Coeliac disease is not limited to Europeans; it has been increasingly reported in patients from non-European backgrounds. Not all patients with coeliac disease are underweight, and a significant minority are overweight or obese. Serological testing is non-invasive and should be considered in patients with suggestive symptoms or associated autoimmune conditions, regardless of racial background. Presentation of coeliac disease can be non-specific, and is not limited to gastrointestinal manifestations. A high index of suspicion is required to screen for the condition in patients with predominant extraintestinal presentation.

Paul Lee MB BS(Hons) · Katherine Samaras MB BS(Hons), FRACP, PhD

To the Editor: Gastric volvulus is rare but has been reported increasingly due to greater frequency of upper gastrointestinal tract investigations. Depending on the rotation axis, gastric volvulus can be classified as organoaxial, mesenteroaxial or mixed type. We report a case of laparoscopic mesh repair of a mesenteroaxial gastric volvulus secondary to a transverse colon diaphragmatic hernia. A 50-year-old woman presented with a 10-year history of intermittent epigastric pain and vomiting. Symptoms persisted despite multiple investigations over the years and treatment with proton-pump inhibitors and prokinetic agents. She described weight loss and intolerance to solid food, but her medical history was unremarkable. Gastroscopy revealed an unusual stomach configuration and difficulty was experienced in intubating the pylorus. A barium x-ray showed no gastric herniation, but the stomach had an unusual appearance (Box, A). Manometry studies showed normal gastric muscle activity. The patient underwent a laparoscopy, which revealed a mesenteroaxial intra-abdominal gastric volvulus secondary to the presence of a section of transverse colon caught in a diaphragmatic hernia adjacent to the oesophagus (Box, B). The colon was reduced and the hernia sac excised (Box, C). The defect in the diaphragm was subsequently closed, and a dual-layered prosthetic mesh was laid over the repaired area. The stomach was repositioned by anterior gastropexy. The patient’s recovery was uneventful and she was discharged on a fluid diet 3 days after surgery. At 4-month review, she was well and a follow-up abdominal computed tomography scan showed no abnormalities. Reports of isolated colonic hiatal hernia are rare.1,2 This case was interesting as it was associated with an intra-abdominal gastric volvulus that presented with chronic symptoms, despite most cases of mesenteroaxial volvulus presenting acutely. Barium studies from 19 patients with colonic herniation through the oesophageal hiatus showed that these hernias were invariably associated with herniation of the stomach, which was partially volvulated in many cases.3 These patients were mostly older women, and did not present in an emergency setting. With growing use of laparoscopic surgery, patients benefit from a minimally invasive approach, decreased pulmonary and wound complications, and faster postoperative recovery. Several authors have reported favourable outcomes after performing laparoscopic diaphragmatic hernia repairs and gastropexy.2,4,5 Our case demonstrates the feasibility of laparoscopic repair of a gastric volvulus secondary to a transverse colon diaphragmatic hernia. Diagnosis and repair of a gastric volvulus A: Barium x-ray of stomach, showing two air–fluid levels that give the impression of an “upside-down” stomach of mesenteroaxial rotation; pylorus (P) and diaphragm (D) are shown. B: Herniated transverse colon (TC) tracking under the liver (L) and into a hernia of the diaphragm. C: Diaphragmatic sac adjacent to the oesophagus, revealed by reducing the colon; oesophagus (O) and stomach (S) are shown.

Kevin Ooi · Christophe Berney

Objective: To investigate the incidence of bariatric surgery and postoperative outcomes in a population-based cohort of patients in Western Australia over a 17-year period.Design and setting: A population-based incidence study of all bariatric procedures (n = 1403) performed in WA hospitals over the period 1988–2004, based on hospital morbidity and death data from the WA Data Linkage System.Main outcome measures: Changes in incidence of bariatric procedures over time; mortality and complications within 30 days after surgery; survival rates after surgery relative to age-, sex-, and period-matched survival rates in the general population; factors predictive of re-admission to hospital.Results: The incidence of bariatric surgery increased from 1.2 procedures per 100 000 person-years in 1988 to 24.2 procedures per 100 000 person-years in 2004. Although some of this was ascribed to a rising prevalence of obesity generally, there was a 13-fold increase in the bariatric procedure rate within the obese population itself. At 5 years, the relative survival rate in bariatric patients was the same as the survival rate in the general population. Within the 30-day postoperative period, mortality was low (0.07%) and 9.6% of patients experienced complications. Those who had bypass-type procedures were more likely to be re-admitted within 30 days than those who had gastric reduction procedures (adjusted hazard ratio, 5.80 [95% CI, 3.42–9.84]).Conclusion: The use of bariatric surgery increased 20-fold over the study period. Relative survival after surgery was in line with population norms. The observed low mortality rates and moderate level of complications are similar to findings in other studies in which the proportion of reduction procedures has been high.

Fiona J Smith BHlthSc(Hons) · C D’Arcy J Holman MB BS, MPH, PhD · Rachael E Moorin GradDipHlthEcon, MSc, PhD · David R Fletcher MB BS, MD, FRACS

To the Editor: We read with interest the article by Rosenfeld and Duggan,1 who speculate on the possible psychological downsides of colorectal cancer (CRC) screening with faecal occult blood testing, and possible barriers preventing women accessing screening. We are concerned that the article has multiple limitations, and would like to report prospective data on CRC screening in Australia. While not mentioning three studies showing no long-term psychological harm from CRC screening,2 the authors have chosen to quote anecdotes from breast cancer screening, and a study of diagnostic testing for hepatitis C in a high-risk population, which is not a population screening test. Further, in the quoted study by Mant et al,3 an example they give of anxiety after a screening test, they neglected to mention that 98% of participants with false positive results felt the test worthwhile, and almost 40% were more likely to take part in other screening. The quoted reduction of 16% in CRC mortality is from one trial only, and potentially misleading as, overall, the studies have shown a 15%–33% reduction in mortality.2 Benefit also goes well beyond reduced mortality, as the 20% reduction in incidence2 with early detection averts some of the physical and financial costs of surgery, radiation therapy and chemotherapy. Further, there are the definite negative impacts of dealing with the consequences of surgical management of a more advanced-stage symptomatic cancer (such as colostomy bags), compared with a screen-detected cancer managed by simple polypectomy. The additional negative effects of diagnosis of a potentially terminal illness are also relevant. Data on participation in CRC screening are available from two sources. The National Bowel Cancer Screening Program evaluations to date have shown that significantly more women participate in the screening offer than men.4 Data from a multicentre Australian prospective CRC database5 reveal 56 of 619 cases in women (9.0%) and 65 of 759 cases in men (8.6%) were detected by screening. Australia has been slow to adopt CRC screening despite the almost 5000 deaths annually, and the major potential benefits. Unlike Rosenfeld and Duggan, we argue that studies specific to CRC screening show no clear negative impact, and that the negative impacts of not screening are undisputed. Also, the available data indicate that women are participating in CRC screening to a greater extent than men.

Suzanne Kosmider · Kathryn M Field · Finlay A Macrae · Peter Gibbs

To the Editor: The recent call by Robotin and colleagues for a national strategy to respond to the increasing incidence of hepatitis B and hepatocellular carcinoma (HCC) in Australia1 is timely. I would like to add the following comments. First, a comprehensive Australian hepatitis B strategy should include prisoners and Indigenous Australians. Among Australian prisoners, hepatitis B carrier prevalence is 3%–5% — more than three times the national average — and prevalence of hepatitis C, which independently and synergistically increases the risk of severe liver disease, exceeds 30%.2 In addition, of 526 acute hepatitis B notifications in Australia in 2000–2002, 57 were in Indigenous Australians, a notification rate more than four times that in non-Indigenous Australians. Indigenous people are 12 times more likely to die of liver cancer than the general Australian population.3 Second, in New South Wales, the median age of diagnosis of HCC was found to vary significantly by country of birth;4 it was 5 years younger in the Asian-born group than the Australian-born group overall (64 v 69 years), and 9 years younger in those who were hepatitis B carriers (57 v 66 years) (P < 0.001 for both differences). Early onset of HCC among Asian-born Australians may be a result of hepatitis B infection in the perinatal and early childhood period. However, other factors that promote progression to HCC, such as diabetes, alcoholism, and inadequate health care access, are amenable to targeted public health interventions. Third, hepatitis B e antigen (HbeAg) positivity is strongly associated with high hepatitis B virus DNA counts (≥ 100 000 copies/mL), which are in turn highly predictive of cirrhosis and HCC risk. It is thus counterintuitive that — as implied by Robotin et al — hepatitis B carriers who are positive for HbeAg are less likely to progress to cirrhosis and HCC than those who have undergone seroconversion and are positive for hepatitis B e antibody. In fact, HBeAg positivity is associated with increased risk of HCC and liver-related mortality.5,6 Finally, the omission of hepatitis B vaccine — the world’s first anticancer vaccine — from Robotin et al’s list of elements of a public health response to hepatitis B and liver cancer is unfortunate. Hepatitis B vaccination is essential to any credible medium- and long-term strategy to prevent hepatitis B infection and, by extension, HCC, both in Australia and globally.

Niyi Awofeso

In reply: We agree with Awofeso that prisoners and Indigenous people have an increased risk of developing chronic hepatitis B. However, as no large-scale population-based studies of hepatitis B prevalence have been published in Australia, estimates of the risk vary widely.1 A national hepatitis B strategy may provide additional impetus for obtaining high-quality data. We also concur that modifiable behavioural factors may play a role in the age of hepatocellular carcinoma diagnosis, but differences in clinical course between Asian and white Australians,2 and the specific viral genotypes prevalent in Asia,3 are likely to be more important. Although white populations who undergo hepatitis B e antigen (HbeAg) seroconversion and develop hepatitis B e antibodies have a good prognosis, this is not so for Asian populations,2 or for other populations who are mostly infected in childhood, such as Indigenous Australians and Māori in New Zealand. The median age of HBeAg seroconversion in Asian patients with chronic hepatitis B is 34.5 years,4 while the median age at diagnosis of hepatocellular carcinoma of Asian patients quoted by Awofeso is 57 years, by which age most would have seroconverted. Australia has been successful in primary prevention of hepatitis B through vaccination (albeit less so in migrants, some Indigenous communities and catch-up vaccination), and hence the omission of vaccination from our “wish list” for a public health response. However, Australia has been less successful in secondary and tertiary prevention. We hope that a national strategy would be a catalyst for these interventions to be given the priority they deserve.

Monica C Robotin · Jacob George · Rajah Supramaniam · Freddy Sitas · Andrew G Penman

To the Editor: A 26-year-old woman presented with 24 hours of severe constant epigastric pain and vomiting. She had no history of similar pains, alcohol consumption or gallstones. Four days before presentation she had received her first dose of human papillomavirus (HPV) vaccine. Two days after vaccination she developed a fever and self-limiting rash of 3 days’ duration. Examination revealed marked epigastric tenderness and temperature of 40°C. Other physical parameters were within normal limits. Biochemical investigations showed normal liver function, moderate leukocytosis, a serum amylase level of 1900 U/L (reference range [RR], 23–85 U/L) and lipase level of 3400 U/L (RR, 0–160 U/L). An upper abdominal ultrasonography showed a non-dilated biliary tree and no evidence of gallstones. Computed tomography showed an oedematous pancreas with peripancreatic fat stranding and arterial enhancement of the pancreatic parenchyma, consistent with pancreatitis without necrosis (Box). Other investigations showed normal serum levels of calcium, triglycerides and parathyroid hormone. Serological tests were negative for acute infection with coxsackie A9, coxsackie B1–6, echo, mumps, herpes simplex, hepatitis and varicella zoster viruses. The patient was diagnosed with pancreatitis and treated conservatively with intravenous fluids and analgesia. Pain, symptoms and biochemical abnormalities settled after 10 days. She was discharged and remains well. Magnetic resonance cholangiopancreatography performed after discharge showed no pancreatic parenchymal or ductal abnormality. Acute pancreatitis is common, with an incidence of 5.4–80 per 100 000.1 Gallstones and alcohol use account for 70%–85% of cases; other causes include drugs, viral infections, tumours, hyperlipidaemia, hypercalcaemia, trauma, iatrogenic injury and pancreatic ductal anomalies. The cause is unidentified in up to 10% of cases.1,2 Viral pancreatitis is well recognised, with cytomegalovirus and mumps, coxsackie, hepatitis, herpes simplex, and varicella viruses all known causes.3 Vaccines have been implicated, with pancreatitis associated with measles–mumps–rubella and hepatitis A and B vaccines.4,5 To date, there has been no report linking HPV vaccination with pancreatitis. The pathophysiology linking vaccination with pancreatitis is unclear. It has been postulated that viral replication in immunodeficient hosts receiving live attenuated viral vaccines can cause pancreatitis. Alternatively, “molecular mimicry” could stimulate production of auto-antibodies, which react with host antigens and cause autoimmunity.5 The HPV vaccine is a quadrivalent, recombinant, non-infectious formulation, eliminating viral replication as a mechanism of pancreatitis. Therefore, an autoimmune mechanism is possible. Extensive clinical testing has demonstrated the safety of HPV vaccine in the general population. In our patient, intensive history taking and investigation failed to identify another cause for pancreatitis, and the close temporal relation of the HPV vaccination, the development of a prodromal illness, and fever without evidence of sepsis led us to postulate that pancreatitis was secondary to vaccination. A coincidental illness causing pancreatitis cannot be ruled out, but neither can HPV vaccination be excluded as a potential cause. We therefore suggest that pancreatitis be considered in cases of abdominal pain following HPV vaccination and if proven, notified to the Adverse Drug Reactions Advisory Committee. Computed tomography scan of the abdomen in a patient with pancreatitis Portal venous computed tomography images showing oedematous enlargement of the pancreas, with surrounding fat stranding and ascites. The pancreas (arrows) appears fully enhanced with contrast, suggesting there was no necrosis. A: Pancreatic head. B: Pancreatic body and tail.

Amitabha Das · David Chang · Andrew V Biankin · Neil D Merrett

To the Editor: We read Pham and colleagues’ recent article1 with interest, as evidence mounts against the use of probiotics in critically ill patients. Although a plausible and attractive theory, probiotics in the patient with acute illness now appear ineffective, if not positively harmful. A recent randomised trial of probiotics in 298 patients with severe acute pancreatitis showed a non-significant rise in infective complications,2 in keeping with results of previous studies of critically ill patients.3,4 Disturbingly, mortality in the probiotic group was more than double that in the placebo group (P < 0.01). Bowel ischaemia was a prominent feature of deaths in the probiotic group (eight patients), but was not associated with any deaths in the placebo group (P < 0.004). It may be that non-occlusive mesenteric ischaemia in critical illness is exacerbated by the added bacterial load itself, or through a pro-inflammatory response by gut epithelial cells. While probiotics may be a benign and beneficial adjunct to enteral feeding in certain clinical situations, there is persuasive evidence that probiotic therapy is associated with increased infective complications in critically ill patients and significant mortality in patients with severe acute pancreatitis. Until there is evidence to the contrary, we believe probiotics should not be administered to patients with severe acute illness.

Shimonti Chatterjee · John Fraser

To the Editor: Pham and colleagues commented on the effects of probiotics; however, not much is known about the impact of probiotics on weight gain and obesity. It is known that a predominance of certain bacteria, such as Lactobacillus, in the bowel can promote weight gain. Many of these bacteria are found in probiotic products. The human intestinal microbiota is predominantly colonised by the Firmicutes and Bacteroidetes phyla of bacteria. Lactobacillus and Bifidobacterium, found in a number of probiotic products, belong to the Firmicutes phylum. A study has shown that obese people carry a higher proportion of bacteria from the Firmicutes phylum and that there is a statistically significant decrease in the proportion of Firmicutes bacteria as they lose weight.3 A similar pattern of Firmicutes predominance has been found in obese mice. Furthermore, the microbiota of the obese mice were more likely than those of lean mice to break down otherwise indigestible polysaccharides from the diet.4 In other words, a higher proportion of Firmicutes bacteria was associated with increased and more efficient caloric uptake from food. These data did not necessarily imply causation, so the investigators performed another experiment. They transferred intestinal microbiota from obese and lean donor mice to germ-free mice, and found that the mice who received microbiota from the obese donors had a significant increase in body fat after 2 weeks compared with the recipients from the lean donors.4 It is therefore likely that the bacteria often found in probiotics can cause weight gain. Obesity in children and adults is a major health problem in developed nations. Given the increasing use of probiotic products in such countries, large studies should be performed to characterise the association between probiotics and obesity. Such studies may not find any association or may find that there is only a dose-related risk. If there is an association, probiotics may still prove useful in certain circumstances (eg, for weight gain in children failing to thrive).

Sanjaya N Senanayake

In reply: The comments by Chatterjee and Fraser regarding the danger of administering probiotics to patients with acute severe illnesses are important additions to the debate on the risks and benefits of probiotic administration. We also thank Senanayake for his interesting comments on the possible role of probiotics in weight gain. The recently published multicentre trial1 describing unexpected adverse events associated with probiotics in acutely unwell patients with severe pancreatitis is one example of an adverse outcome following probiotic administration. The use of probiotics in patients with severe comorbidities and in those who are immunocompromised is also contraindicated. There are reported cases of Lactobacillus GG sepsis in premature babies with short gut syndrome,2 and Saccharomyces boulardii fungaemia has been described in immunocompromised patients.3 It is interesting to note that two systematic reviews have assessed the efficacy of probiotics in prevention of necrotising enterocolitis in premature (< 33 weeks’ gestation) and very low birthweight (< 1500 g) infants.4,5 Both reviews concluded that probiotics may decrease the incidence of necrotising enterocolitis in preterm infants, and that severe adverse events were not associated with probiotics in these unwell and immunodeficient patients. However, there were insufficient data to comment definitively on the short-term or long-term safety of probiotics in these infants; this will require assessment in future large trials. The increased scrutiny of probiotics resulting from the publication of the adverse outcomes in adults with severe acute pancreatitis1 may, by necessity, slow the commencement and progression of these larger trials in infants in the neonatal intensive care setting.

Mimi Pham · Daniel A Lemberg · Andrew S Day

A 64-year-old man presented with abdominal distension and nausea, following 5 days of colicky abdominal pain and constipation. He had been taking antihypertensive and anti-asthma medication for 15 years. Clinically, generalised abdominal tenderness and guarding were present. A chest x-ray revealed hepatodiaphragmatic interposition of the large bowel (Chilaiditi sign). Abdominal computed tomography confirmed the presence of bowel loops anterior to the liver (Figures, arrows) and grossly dilated large bowel with no evidence of pneumoperitoneum. Biochemical analysis revealed hyponatraemia and hypokalaemia. No evidence of mechanical bowel obstruction was found during surgery. The final diagnosis was acute colonic pseudo-obstruction (Ogilvie syndrome) with Chilaiditi syndrome. To our knowledge, this is the first report of a patient with both these rare, and possibly correlated, syndromes.

Shobhit Mathur · Om J Lakhani · Virsing P Hathila · Dipesh D Duttaroy · Anis S Vohra · Himesh R Chauhan

A 79-year-old man presented with painless dysphagia. Results of an oesophagogastroduodenoscopy were unremarkable. A dynamic videofluoroscopic examination was diagnostic, revealing hypertrophic cervical osteophytes indenting the hypopharynx and oesophagus. The osteophytes were also seen on a lateral cervical spine radiograph (Box). The dysphagia responded to dietary modification. Although cervical osteophytes are seen in 20%–30% of the geriatric population, they are an unusual (and treatable) cause of dysphagia. Dysphagia occurs because of mechanical blockage as well as inflammation of the peripharyngeal and peri-oesophageal tissue. As enlarged cervical osteophytes may be an incidental finding, it is important to exclude other potential causes, such as neoplasm.1,2 Lateral radiograph of the cervical spine showing multiple enlarged anterior and bridging cervical osteophytes, with the most prominent bridging osteophyte between the C4 and C5 vertebrae (arrow).

Shoaib Faruqi · Muthu Thirumaran · Parry Blaxill

To the Editor: A 37-year-old male Sudanese refugee presented with lethargy, nausea, abdominal discomfort and bloating. He had chronic hepatitis B and a 2-year history of hazardous levels of alcohol consumption (90 g/day). On examination, there were no features of chronic liver disease. His liver enzyme levels were elevated (alkaline phosphatase, 189 U/L [reference range (RR), 40–110 U/L], γ-glutamyltransferase, 456 U/L [RR, < 50 U/L], alanine aminotransferase, 51 U/L [RR, < 45 U/L], and aspartate aminotransferase, 53 U/L [RR, < 40 U/L]), but synthetic function was preserved and serum bilirubin level was normal. Hepatitis B virus DNA was 1.3 × 103 IU/mL, consistent with a low-level viraemia, while HBeAg and anti-HBeAb were both non-reactive. His platelet count was reduced (115 × 109/L [RR, 140–400 × 109/L]), suggesting portal hypertension. The remainder of his chronic liver disease screen was unremarkable. Endoscopy revealed four grade 1 oesophageal varices, mild portal hypertensive gastritis, and patchy erosive duodenitis. The irregular liver and periportal fibrosis seen on ultrasound (Box 1) raised the possibility of cirrhosis. Subsequently, a biopsy of the liver showed preserved liver architecture, with periportal fibrosis and active schistosomiasis (Box 2). A diagnosis of Schistosoma mansoni infection was made, based on the histological appearance of the ova. S. mansoni is the leading cause of chronic liver disease and portal hypertension in sub-Saharan Africa.1,2 Adult worms reside in mesenteric vessels, but their migrating eggs lodge in hepatic presinusoidal radicals, resulting in inflammation and granuloma formation. The inflammatory reaction eventually leads to occlusion of portal veins and secondary portal hypertension.3 Hepatocellular function usually remains normal.1 Although the “gold standard” for diagnosis of S. mansoni infection is microscopic examination of faeces, this test may be negative (as it was in this case). Serological screening is recommended, but these assays cross-react with other helminthic infections and are unable to distinguish active infections from previous exposure.1 Praziquantel should be offered to previously untreated patients with positive serology results; after a single dose, 70%–100% of patients cease to excrete eggs.1 In patients who have left S. mansoni-endemic areas, an oral dose of 60 mg/kg split in two and given several hours apart should ensure cure.1 Our patient was treated with praziquantel, with ongoing follow-up for hepatitis B and portal hypertension. In retrospect, the patient’s history and the sonographic appearances were consistent with schistosomiasis. This clinical scenario is of increasing relevance, with a growing number of people from Africa now living in Australia. 1 Liver ultrasound Ultrasound shows an irregular liver with marked periportal fibrosis. There is no intra- or extrahepatic biliary tree dilatation. The portal vein flow is antegrade. No focal hepatic lesion is seen. 2 Liver biopsy specimen Preserved round to oval parasites with ova, some with a refractile exoskeleton and small lateral spine, can be seen. The viable forms suggest active infection. The surrounding inflammation contains numerous eosinophils, with fibrous expansion of the portal tracts. The adjacent liver revealed a preserved architecture with a normal METAVIR score of A0F0 (haematoxylin–eosin stain; low-power [A] and high-power [B] magnification).

James Daveson · Graeme Macdonald

To the Editor: I wish Professor Carr the very best in his attempt to eliminate the somewhat confusing term “Barrett’s oesophagus” from the literature.1 Changing well entrenched medical nomenclature is difficult, however. I tried to do this with “microscopic colitis” 10 years ago2 but was not successful. After all, I argued, we do not speak of “microscopic bronchitis” or “microscopic salpingitis” — so why should we have the term microscopic colitis? It is nonetheless pleasing to note that the definition of microscopic colitis has tightened up over the past 10 years,3 and I think this may be a more realistic aim for Professor Carr with the term Barrett’s oesophagus. Admittedly, the two entities are not perfectly analogous, as, unlike microscopic colitis, Barrett’s oesophagus is classically associated with abnormally coloured mucosa. However, in both entities, the endoscopist usually takes biopsies from endoscopically flat mucosa, specifically looking for the disease in question. I am not sure I can see myself in 10 years’ time looking down someone’s oesophagus and saying, “I think there may be some columnar metaplasia down there. I wonder if there is some intestinal metaplasia as well?” Maybe this would be a good conversation opener in the halls of the pathology department, but certainly not in the endoscopy suite! I think I will still be saying, “That looks like Barrett’s, but we will need to take biopsies to make sure”.

Andrew A Thomson

In reply: I thank Dr Thomson for his kind comments. I sympathise with his attempts to eliminate the term “microscopic colitis”1,2 and would happily join him in this campaign. I agree it is important to tighten up the definitions of ambiguous terms. For example, “indeterminate colitis” is another term that continues to be used in different ways, despite attempts to clarify its definition.3 However, in the case of Barrett’s oesophagus, there are precise definitions, but they are mutually exclusive. The British Society of Gastroenterology uses one definition (not requiring goblet cells), whereas other national bodies use another definition (requiring the demonstration of goblet cells histologically).4 Therefore, when an endoscopist says “That looks like Barrett’s”, he or she could be saying either that the mucosa appears glandular or that a pathologist will find goblet cells in it. The two are not the same and we should not confuse them. I believe we should not use “Barrett’s oesophagus” because it is defined differently by different people; confusion regarding the site of a particular biopsy can cause it to be applied inappropriately; and we have existing terminology that does the job. I accept that a few lone voices are not going to change well entrenched terminology. However, we can hope that the national and international bodies that construct guidelines in this area will take heed, accept the challenge and deal with the problem.

Norman J Carr

Clinical record A 51-year-old woman of European ancestry presented in 2006 with a 2-month history of lethargy, nausea and arthralgia, and 2 weeks of jaundice. Her past history included gastric bypass surgery for obesity at the age of 40 years, and laminectomy. She had been taking a commercial preparation of black cohosh (20 mg per day) intermittently for 3 years, with titration according to her menopausal symptoms. This preparation was available over the counter. It contained 20 mg of black cohosh root extract per tablet, and the manufacturer recommended a dose of 20 mg twice daily. Two months before symptom onset, the patient increased the dose to the manufacturer’s recommended dose because of worsening menopausal symptoms. The patient was not taking any other medications, including other herbal preparations, paracetamol, or non-steroidal anti-inflammatory drugs. She had no personal or family history of liver disease. She was an ex-smoker, with no history of illicit drug use, significant alcohol consumption, recent travel, tattoos, transfusions or sick contacts. Physical examination revealed jaundice and mild ascites, but no evidence of hepatic encephalopathy or stigmata of chronic liver disease. Results of laboratory studies were consistent with acute hepatitis. Serum albumin concentration was 36 g/L (reference range [RR], 31–44 g/L); elevations were noted in serum concentrations of aspartate aminotransferase (AST) (1327 U/L; RR, < 40 U/L), alanine aminotransferase (ALT) (1230 U/L; RR, < 50 U/L), alkaline phosphatase (ALP) (191 U/L; RR, 30–110 U/L), γ-glutamyltransferase (GGT) (523 U/L; RR, < 40 U/L), and bilirubin (106 μmol/L; RR, < 20 μmol/L). The international normalised ratio (INR) was 1.8 (RR, 1.0–1.2), serum creatinine concentration was 58 μmol/L (RR, 45–90 μmol/L) and MELD (Model for End-Stage Liver Disease) score was 16 (a score > 15 indicates that prognosis at 1 year will be improved by transplantation). Extensive investigations to exclude other causes of acute liver failure gave negative results, including serological tests for hepatitis A, B, and C; cytomegalovirus IgM; Epstein–Barr virus IgG and IgM; antinuclear antibody; anti-liver/kidney microsomal antibodies; antimitochondrial antibody; anti-smooth muscle antibody, α-1 antitrypsin; ceruloplasmin; and fasting iron studies. Abdominal computed tomography 1 month after presentation showed moderate ascites and a shrunken irregular liver contour, with a liver volume of 720 mL. Prominent vessels around the lesser curvature of the stomach suggested portal hypertension with collateral vessel formation. Doppler ultrasound examination a month later confirmed a small liver with coarse heterogeneous echotexture, and a macronodular surface. The portal vein was patent. A liver biopsy 6 weeks after presentation showed massive hepatocellular necrosis with preserved bile ducts, collapsed parenchyma, and no recognisable residual hepatocytes (Figures, A and B). There were extensive mononuclear inflammatory infiltrates with few neutrophils. Perls staining was negative for iron. A diagnosis was made of acute liver injury secondary to black cohosh ingestion. Over the subsequent weeks, the patient’s jaundice worsened, and her serum bilirubin level continued to rise. Frusemide was given to manage developing moderate ascites. Sixty-two days after presentation, the patient developed asterixis (“hepatic flap”), indicating encephalopathy and liver failure. She was diagnosed with subfulminant liver failure suitable for liver transplantation and was listed urgently for transplant. Liver function tests showed a serum albumin concentration of 30 g/L and elevated serum concentrations of AST (202 U/L), ALT (73 U/L), ALP (191 U/L), GGT (64 U/L) and bilirubin (728 μmol/L). The INR was 1.8. Her renal function rapidly deteriorated, with serum creatinine concentration rising to 255 μmol/L. The MELD score reached 37. A liver became available 5 days after the patient was listed, and a successful orthotopic liver transplantation was performed. Her postoperative course was uneventful. The explanted liver weighed 744 g and was distorted by multiple nodules of varying size, from 5 mm to 50 mm (Figure, C). Microscopically, there were areas of extensive submassive necrosis, capsule distortion, collapse of the hepatic parenchyma, and mononuclear inflammatory infiltrates around the portal tracts. Cholestasis was prominent. Nodular regeneration with portal–portal linkage was also evident in some areas, as seen in the pretransplant biopsy. Black cohosh is a herbal remedy used around the world for relief of menopausal symptoms. In Australia, over 200 listed medicines containing black cohosh are available without prescription.1 However, in the past decade, seven case reports of hepatotoxicity associated with black cohosh have been published.1-7 To our knowledge, our patient is the eighth reported case, and the sixth to require liver transplantation. Lessons from practice Black cohosh is a herbal remedy used by millions of women worldwide for the relief of menopausal symptoms. Emerging evidence of severe hepatotoxicity potentially linked with the use of black cohosh has raised concerns regarding its safety profile. The community needs to be educated about potential risks of alternative and herbal medications such as black cohosh, and further regulations are required to monitor the safety of these preparations. Black cohosh (Cimicifuga racemosa, also known as Actaea racemosa) is a perennial plant native to North America. The World Health Organization recognises its use for “treatment of climacteric symptoms such as hot flushes, profuse sweating, sleeping disorders and nervous irritability”.8 The American College of Obstetricians and Gynecologists stated that it may be helpful in the short term (6 months or less) for women with vasomotor symptoms of menopause.9 Although the exact mechanism of action is unknown, the primary active constituent of the black cohosh root is the terpene glycoside fraction, and the rhizome contains biologically active substances, including alkaloids, flavonoids, and tannins. However, despite the growing literature on the efficacy of black cohosh for menopausal symptoms, definite conclusions cannot be drawn because of the methodological shortcomings of available studies, such as lack of blinding, lack of long-term follow-up, and variations in product and dosage.10-12 Two safety reviews have found black cohosh extract to be well tolerated and adverse events to be rare when it is taken for up to 6 months.13,14 However, the seven case reports of hepatotoxicity potentially associated with black cohosh use in the past decade raise concern. Currently, there is no known biologically plausible mechanism to explain this hepatotoxicity, which is likely to be multifactorial. The plant contains both potentially hepatoprotective (triterpene glycosides) and hepatotoxic (salicylates, alkaloids) elements. Extracts and constituents of the rhizome have been shown to induce apoptosis and cell cycle arrest in human breast cancer cells,15,16 while extracts of the related plants Cimicifuga foetida and Cimicifuga dahurica inhibited proliferation of rat and mouse hepatocytes.17 The most likely cause of our patient’s liver failure was her use of black cohosh, although it has been recognised that 10% of patients receiving liver transplantation have idiopathic subfulminant liver failure.18 Our patient’s history of obesity treated with gastric bypass surgery 11 years before is unlikely to have contributed to the liver failure as she had shown no abnormalities of liver function previously, and no features of steatohepatitis were seen in the pretransplant liver biopsy specimens. Our case is also notable as the patient had used black cohosh intermittently at half the manufacturer’s recommended dose for 3 years, and at the manufacturer’s recommended dose (20 mg twice a day) for only 2 months before symptom onset. There is a widespread belief in the community that “natural” plant substances are safe, effective and free of side effects. Various regulatory bodies now recognise the association between black cohosh use and hepatotoxicity, and many recommend warning labels. The Therapeutic Goods Administration (TGA) was the first in the world to announce, in February 2006, that medicines containing black cohosh must include the label: “Warning: black cohosh may harm the liver in some individuals. Use under the supervision of a healthcare professional”.19 In November 2007, the TGA revised the warning to: “In very rare cases, black cohosh has been associated with liver failure. If you experience yellowing of the skin or eyes, dark urine, nausea, vomiting, unusual tiredness, weakness, stomach or abdominal pain, and/or loss of appetite, stop using this product and see your doctor”.20 Randomised controlled trials will provide more definitive information on the safety of black cohosh and its efficacy for alleviating menopausal symptoms. Animal models may provide useful information about the cause of idiosyncratic liver damage. The public needs to be educated about the potential risks of alternative and herbal medications, and further regulations are required to monitor the use and safety of these preparations. Currently, there are no agreed guidelines for monitoring liver function in patients taking black cohosh. We recommend that liver function be checked before and during use of black cohosh.

Elizabeth C-Y Chow MD · Marcus Teo MB BS · John A Ring MB BS, PhD · John W Chen MB BS

Clinical recordA 35-year-old British man was admitted with a 2-week history of abdominal discomfort, fatigue and intermittent high fevers associated with drenching night sweats. He reported having returned to Australia 2 months before presentation from a 12-year around-the-world trip, having travelled extensively for 6 months through South-East Asia and northern Australia. Before that, he had been to Argentina, the Maldives, Egypt, India and Cambodia, where he had worked as a professional kitesurfing instructor. His past medical history was unremarkable and he was not on regular medication. His social history revealed intravenous heroin addiction in his early 20s. He had consumed more than 80 g of alcohol daily for a number of years, with occasional binges, until recently, when drinking alcohol provoked nausea and vomiting. The patient appeared unwell with a tympanic temperature of 40°C. He was fair-skinned and of muscular build. Physical examination showed conjunctival jaundice but no evidence of needle tracks, rashes, finger clubbing, lymphadenopathy or suspicious cutaneous lesions. Tender hepatomegaly was noted, but no ascites or splenomegaly. Findings of cardiac, respiratory and neurological examinations were normal. Abnormal laboratory findings on admission were: albumin concentration, 29 g/L (reference range [RR], 33–47 g/L); alkaline phosphatase titre, 164 U/L (RR, 30–115 U/L); γ-glutamyl transferase titre, 207 U/L (RR, 0–45 U/L); alanine aminotransferase titre, 76 U/L (RR, 0–40 U/L); aspartate aminotransferase titre, 279 U/L (RR, 0–40 U/L); lactate dehydrogenase titre, 4268 U/L (RR, 100–225 U/L); white cell count, 13.4 × 109/L (RR, 4.0–11.0 × 109/L); absolute neutrophil count, 9.7 × 109/L (RR, 1.5–6.0 × 109/L). There was no evidence of thrombocytopenia, renal dysfunction or coagulopathy. Findings on abdominal ultrasonography the day before admission were reported to be normal. Despite there being few clinical features to suggest a source of sepsis apart from the hepatomegaly, because of his travel history and previous history of injecting drug use, a wide variety of infectious diseases, including subacute bacterial endocarditis, typhoid, malaria, and viral hepatitis, were all initially considered in the differential diagnosis. Multiple sets of blood cultures, urine and stool samples were sent for microscopy, culture and sensitivity. Three sets of thick and thin films for malaria as well as a test for Plasmodium falciparum antigen were negative. In view of the clinical hepatomegaly, a computed tomography (CT) scan of the abdomen was performed, which was reported as strongly suggestive of microabscesses (Box). The presumptive diagnosis at this stage was a tropical pyogenic liver abscess, although military tuberculosis and candidiasis were also considered. Intravenous therapy with flucloxacillin, ceftriaxone, ciprofloxacin and metronidazole was initiated. The ceftriaxone was subsequently changed to meropenem, and the ciprofloxacin ceased 5 days after there had been no growth on any cultures. Serological tests for a wide variety of pathogens and diseases were also performed, including: HIV 1 and 2; hepatitis viruses A, B and C; cytomegalovirus; Epstein–Barr virus; Q fever; brucellosis; cryptococcosis; Entamoeba histolytica; Ross River virus; Dengue virus; flavivirus; leptospirosis; schistosomiasis; cysticercosis; and melioidosis. Results for all of these eventually returned negative. Despite the antibiotics and fluids given intravenously, the patient’s condition deteriorated over the course of 6 days and he developed hepatic encephalopathy, ascites, pleural effusions and peripheral oedema. He also continued to spike high temperatures daily, but repeated blood cultures were sterile. A CT scan performed a week after the initial CT scan suggested enlargement of the liver lesions. Although hepatic abscesses were still considered most likely, given the markedly elevated lactate dehydrogenase titre and lack of clinical improvement with broad-spectrum antibiotic therapy, alternative diagnoses, in particular malignancy, were also considered. We therefore performed a core biopsy of the liver under ultrasound guidance. There was no evidence of pus, and the lesional tissue showing strong monoclonal antibody staining against Melan-A and HMB-45 confirmed liver infiltration by a poorly differentiated malignant melanoma. Repeat physical examination included dilated pupil fundoscopy, which showed a brown, dome-shaped subretinal lesion just below the left optic disc, most suggestive of a primary choroidal melanoma. The patient said that he never used sunglasses while kitesurfing. DiscussionExposure of the unprotected eye to sunlight or sunlamps is an important risk factor for the development of intraocular melanoma.1 The incidence of ocular melanoma in dark-eyed individuals is lower, probably because they are less sensitive to solar radiation, or less is transmitted to the choroids.2 Uveal melanoma (affecting the iris, ciliary body, and choroids) is the most common primary intraocular malignancy in the Western world, affecting six to eight adults per million each year. Although fewer than 2% of patients show evidence of metastatic spread at presentation, over 40% will eventually die from widespread disease.3 Most intraocular melanomas are initially asymptomatic. Tumour enlargement may then cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or decreased visual acuity caused by either central growth close to the macula or secondary retinal detachment (choroidal melanoma). Because the uveal tract is a vascular structure without lymphatic channels, tumour spread occurs primarily by either local extension or by haematogenous dissemination. The first site of systemic metastases is the liver, although spread to other organs such as lung, bone, and subcutaneous sites have been described.3 Metastasis of melanoma to the liver, although rare, can produce a dramatic initial presentation with fulminant hepatitis, shock, and multisystem organ failure.4 An elevated lactate dehydrogenase titre is one of the most predictive factors for metastatic spread and decreased survival in patients with malignant melanoma, with a sensitivity of 79% and specificity of 92% in detecting disease progression to stage IV melanoma.5 Extraocular extension and metastatic spread are associated with an extremely poor prognosis, and response rates with contemporary single-agent chemotherapy are generally below 10%. A recently published study investigated the use of chemotherapy with intra-arterial hepatic fotemustine.6 Median survival rates were among the longest reported, with an overall response rate of 36%, a median overall survival of 15 months, and a 2-year survival rate of 29%. Our patient was scheduled for three cycles of intravenous fotemustine therapy, but developed significant tumour lysis syndrome with intractable hyperkalaemia. He died shortly after the second cycle, only 28 days after being admitted to hospital. The final diagnosis was hepatic failure secondary to metastatic melanoma from an intraocular primary melanoma. An autopsy was not performed. Coronal reconstruction computed tomography image of the abdomen showing hepatomegaly with numerous low-density lesions scattered throughout both lobes of the liver

Stefan Buchholz MD, MRCP(UK) · George Rudan MB BS, FRACP

Straightforward, unambiguous terminology can reduce the risk of labelling patients inappropriately Whenever the definition of a diagnostic term is changed, a Pandora’s box of potential confusion is opened. Are all clinicians and research investigators using the same criteria? If a patient has been given a diagnostic label, does it refer to the old or the new definition? Barrett’s oesophagus has changed its definition more than once over the past five decades and is a prime example of how changing definitions causes confusion for clinicians and investigators alike.1,2 A solution to this problem lies in avoiding the potentially confusing term “Barrett’s oesophagus” altogether. Moreover, this is possible by using existing terminology without the need for any new definitions. Historical perspectiveBarrett’s oesophagus takes its name from Norman Barrett, who published on the subject in 1950.1,2 He observed that, in some individuals, the oesophagus is lined by glandular rather than squamous mucosa, and he assumed, like some earlier investigators, that a congenitally short oesophagus had drawn the stomach into the thorax. However, within a few years studies had shown that this columnar-lined tubular structure was not stomach, but true oesophagus characterised by submucosal glands and muscularis propria typical of the oesophagus. Furthermore, it often had islands of squamous epithelium. Since it was assumed that the presence of gastric mucosa in the distal oesophagus might be a normal occurrence, early investigators into the phenomenon wished to avoid false positive diagnoses by excluding anyone who might have putatively normal glandular mucosa at the distal end of the oesophagus, and thus ensure that only patients who really did have metaplastic glandular mucosa were included in their studies. They therefore set arbitrary criteria for the length of columnar lining in the tubular oesophagus required for a diagnosis of Barrett’s oesophagus; some investigators stipulated 3 cm, others 2 cm.1 During the 1960s, clinicians adopted these inclusion criteria as literal definitions of Barrett’s oesophagus, and considered glandular mucosa in the distal 3 cm or 2 cm of the oesophagus to be normal. However, there is very little evidence that gastric mucosa normally extends proximal to the anatomical gastro-oesophageal junction, and some researchers believe that any such extension is abnormal (ie, columnar metaplasia).2,3 These early studies established that glandular metaplasia of the distal oesophagus is caused by reflux, and that the normal mucosa is replaced by a mosaic of glandular epithelium of various types: cardiac, intestinal, and/or gastric fundic with parietal cells.2,4-7 The general term “columnar metaplasia” is appropriate for all three types. However, in the 1980s it became clear that the risk of developing adenocarcinoma was particularly associated with the intestinal type of epithelium.8 As a result, researchers whose major focus was the oncogenic potential of the condition defined Barrett’s oesophagus as the presence anywhere in the oesophagus of intestinal metaplasia (IM), as shown by the presence of goblet cells in histological sections.1 Clinicians again followed the cue of the researchers, and the definition changed once more so that Barrett’s oesophagus became synonymous with oesophageal IM. This concept has been refined, and the definition promulgated by a number of international consensus conferences is that Barrett’s oesophagus is diagnosed when columnar epithelium containing goblet cells is found in a biopsy from mucosa having the endoscopic features of Barrett’s oesophagus.4,7,9-11 Current usage of “Barrett’s oesophagus”Despite this definition, the requirement for goblet cells has not been applied consistently. Some pathologists continue to use the term Barrett’s oesophagus for any glandular mucosa in the true oesophagus, whether it be of fundic, cardiac, or intestinal type. This position seems to have been more common in the United Kingdom, and recent guidelines issued by the British Society of Gastroenterology explicitly state that IM is not necessary for the diagnosis.12,13 The rationale is that sampling errors at endoscopy may miss foci of IM, but that essentially all patients, at least those with long-segment disease, will show IM at some time if enough biopsies are taken.13 However, there is evidence that this assumption may be erroneous: in a large population-based study in Northern Ireland, patients with columnar metaplasia of the oesophagus had an increased risk of developing adenocarcinoma only if IM was found; furthermore, there was 93% concordance between IM status on the first biopsy and any subsequent biopsy.14,15 These results suggest that some patients simply do not exhibit IM in their columnar-lined oesophagus, and that biopsies are able to divide patients into well stratified risk groups based on this fact. Consistent with this conclusion are the observations of others that even multiple biopsies, especially in short-segment disease, sometimes contain no goblet cells.16 It is unfortunate, to say the least, that doctors in different parts of the world should be using completely different diagnostic criteria. The potential for miscommunication between clinicians and researchers is obvious. The problem of oesophagus versus stomachA significant practical diagnostic problem arises if Barrett’s oesophagus is defined by the presence of IM, because the diagnosis is only correct if the biopsy specimen showing IM comes from the oesophagus (ie, mucosa that was previously squamous) and not from the stomach. This distinction is important because, despite the methodological problems that plague studies in this area, there is evidence that IM of the proximal stomach is different clinically and pathologically from IM in the oesophagus. Therefore, “Barrett’s oesophagus” should be avoided if the specimen might have come from the stomach, because the diagnostic label could imply the wrong disease process. In particular, compared with IM in the gastric cardia, IM in the oesophagus is more likely to be associated with reflux and more likely to become dysplastic.17 On the other hand, patients with IM of the gastric cardia are more likely to have Helicobacter pylori gastritis. Some immunohistochemical markers have been found to show a difference between gastric and oesophageal IM, including DAS-1 and CDX2,18-20 and differences in expression of the cytokeratins CK7 and CK20 have been described by some researchers (although not all).21,22 Unfortunately, despite these and other differences between IM in the oesophagus and IM in the stomach, no histological technique has yet been shown to reliably distinguish IM in the two sites in clinical material.4,13,18 There is one exception: if the pathologist observes a feature specific for the oesophagus (eg, a submucosal gland or its duct), then origin from the oesophagus can be definitively stated. However, this is only likely if jumbo forceps are used, and even then it only occurs in some cases.10 In general, the only way in which the pathologist can tell where the biopsy came from is by the endoscopist providing the information. Hence the problem — clinicians do not always give accurate information on the request form regarding the site of the biopsy. Pathologists may try to get around this problem by making statements such as: “The biopsy appearances would be consistent with Barrett’s oesophagus if the biopsy came from the true oesophagus”. Consequently, there is a risk that patients will be inappropriately labelled with the diagnosis of Barrett’s oesophagus through miscommunication. There is a controversy regarding the cardiac mucosa that touches on this discussion. Some researchers have suggested that cardiac mucosa (ie, mucosa composed of glands without oxyntic cells at the gastro-oesophageal junction) is always abnormal, and represents a change due to reflux.2,3 According to this hypothesis, only oxyntic mucosa is normal in the proximal stomach, only squamous mucosa is normal in the oesophagus, and what most people call cardiac mucosa is actually a pathological change (“reflux carditis”). A consequence of this is that finding cardiac mucosa in a biopsy would automatically imply that the specimen came from the oesophagus, not the stomach.2,3 However, the idea that there is no such thing as normal cardiac mucosa is a minority opinion and is not supported by the conclusions of studies showing that the gastric cardia in individuals defined as normal is usually lined by pure mucous glands or a mixture of mucous and oxyntic glands for up to 4 mm.23-25 The solutionA solution to these problems of inconsistency and confusion is to stop using the term “Barrett’s oesophagus” altogether, and instead use alternative terms that are less ambiguous. A biopsy from the oesophagus showing IM could be diagnosed as “columnar metaplasia with intestinal metaplasia”, while one without IM could be labelled “columnar metaplasia without intestinal metaplasia”. This terminology is based on well established usage and does not depend on subscribing to a particular definition of Barrett’s oesophagus; it avoids the problem of variable definitions, and the risk factor of IM is clearly and unambiguously stated. In any case, avoiding the term Barrett’s oesophagus should be routine if the biopsy site is unclear, because it implies a risk of neoplasia that would be incorrect if the biopsy came from the stomach. A diagnosis such as “glandular mucosa with intestinal metaplasia” combined with a statement in the pathology report about the uncertainty of the exact site of the biopsy would eliminate the potential misunderstanding that could arise if the word Barrett’s appeared. One could argue that a general term to describe the various morphological changes in the vicinity of the gastro-oesophageal junction remains useful. However, using “Barrett’s oesophagus” in this way is inappropriate because it now has precise definitions — even though these definitions have significant regional differences. One could also suggest that appropriate education is all that is required to allow Barrett’s oesophagus to be diagnosed correctly. Nevertheless, we still need to know which definition is being used before we can understand what a colleague means by Barrett’s oesophagus. It would be much simpler just to say what we mean using straightforward words. Others have suggested this solution before (including Norman Barrett himself),1 yet it does not seem to have been widely adopted. Although it might take a long time to eliminate a term as entrenched as Barrett’s oesophagus, the medical community has successfully negotiated changes in diagnostic terminology many times before. In this case, no new definitions would be required — simply the application of expressions we already understand.

Norman J Carr MB BS