Subdividing functional dyspepsia: a paradigm shift?

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Commentary

Subdividing functional dyspepsia: a paradigm shift? Nicholas J Talley An understanding of functional dyspepsia (FD) has remained elusive in part because defining the condition has been so difficult.1–3 The term dyspepsia (or ‘‘bad digestion’’) was simply derived from the Greek dys which means ‘‘bad’’ and peptein which means ‘‘to digest’’.3 FD in 2008 is still a diagnosis of exclusion1; the synonyms endoscopy-negative or non-ulcer dyspepsia are arguably no more illuminating. To confound the situation further, the word dyspepsia is not understood by most patients, but remains a vague term in common medical parlance.1–3 There has been an evolution in thinking in terms of what symptoms should and should not comprise FD, but there remains a lack of global consensus despite the Rome working team reports.4 Thus, the recent National Institute for Health and Clinical Excellence (NICE) guidelines in the UK continued to lump symptoms of gastro-oesophageal reflux disease (GORD) in with all other upper abdominal complaints as ‘‘dyspepsia’’ in contrast to US guidelines.4 5 Prior to the Rome consensus process, dyspepsia was so poorly defined that the literature was arguably impossible to interpret.3 Many studies used the expression but failed to report what they meant by dyspepsia.6 7 The bandying around of fuzzy concepts persisted—for example, defining dyspepsia as that group of symptoms triggered when food digestion was disordered3 (but how does one know food digestion is truly disordered?). Dissimilar conditions were subsumed under this heading, including GORD and biliary pain, to name a few.3 The simple concept that dyspepsia should be restricted to refer to meal-related symptoms was largely dismissed because not all peptic ulcer patients reported clear-cut meal-related complaints.3 With the rapid disappearance of peptic ulcer disease in many parts of the Western world, there is now little interest in understanding the exact pathogenesis of symptoms in this condition. On the other hand, there is increasing interest in FD as it remains Correspondence to: Professor Nicholas J Talley, Mayo Clinic 4500 San Pablo Road, Davis 6-72E, Jacksonville, FL 3224, USA; [email protected] Gut November 2008 Vol 57 No 11

remarkably common, affecting an estimated 15% of the population, in turn inducing a substantial personal and healthcare burden.8 9 The early Rome definitions of dyspepsia refer to persistent or recurrent abdominal pain or discomfort centred in the upper abdomen.2 3 Upper abdominal discomfort was defined as a subjective negative feeling which did not reach a level of pain according to the patient, while centring referred to symptoms mainly localised in the epigastrium although it did not exclude patients who had discomfort or pain elsewhere.2 3 Neither Rome I nor Rome II focused on meal-related symptomatology as central to defining dyspepsia or FD, but did identify a subset of patients who were more likely to present with epigastric pain and another subset who were more likely to present with postprandial discomfort or other non-painful complaints.2 3 5 Subsequent research showed that most patients who presented with the label of dyspepsia have multiple symptoms,10 while factor analysis studies from various populations identified a clear-cut grouping of people who reported meal-related symptoms.11 The Rome III committee reclassified FD; they hypothesised that there is a postprandial distress syndrome (comprising patients with bothersome postprandial fullness or early satiation after most meals), and a separate grouping with epigastric pain or burning which was not meal related (the epigastric pain syndrome), but the validity of this classification remains uncertain.1 In a seminal paper published in this month’s Gut (see page 1495), new data are presented which suggest that true symptoms of dyspepsia are all inducible by a meal.12 These observations have some potentially very important clinical implications for diagnosis and treatment. We all know this is true when we overindulge at dinner time, but Bisschops et al observed that a standard solid meal can induce mild symptoms in health.12 They quantified in controls the symptom burden after their standard meal (a 250 kcal meal with 10 g of fat), and observed that fullness and bloating

significantly increased 15–150 min after meal ingestion. In contrast, patients who fulfilled the Rome II criteria for FD had a much more rapid and greater increase in symptom intensity scores after meal ingestion, which then only gradually decreased. Notably, by 4 h, none of the symptoms had returned to their baseline values in the patients with FD; how long meal-ingested symptoms persist still needs to be documented. Of the 218 patients with FD who were enrolled, only one case did not identify an increase in symptom intensity over the observation period after the meal. Of interest, the symptom peaks for postprandial fullness and bloating occurred sooner after the meal in FD (at ,40 min), while epigastric pain or burning occurred much later but was still clearly meal related. Other evidence supports the view that specific meals can induce symptoms in patients with unexplained dyspepsia. For example, patients will more often experience symptoms after intraduodenal infusions of fat than glucose in experimental human models.13–15 Hence the fat content of the meal may be critical when interpreting the effects of meal ingestion on symptom induction. Notably the numbers studied in these models have been relatively small and, arguably, placing a tube into the duodenum may induce perturbations that could alter the physiology. A key question then arises as to what explains a near universal exaggerated response to meal-induced symptoms in patients with FD? Gastric emptying is slow in approximately 25% of cases with FD and may be accelerated in a further 10%.8 Bisschops et al observed that slow solid gastric emptying was more closely linked to higher scores for meal-induced fullness, bloating and pain than slow liquid emptying.12 However, gastric emptying abnormalities (20% for solids and 31% for liquids) seem rather unlikely to explain meal-related symptoms in this cohort, as the symptom peaks did not differ in those with slow versus normal gastric emptying.12 Other data strongly suggest that there is usually a disconnection between gastric emptying findings and symptomatology.16 Impaired gastric accommodation to a meal and gastric hypersensitivity to distention are other objective findings in FD.8 In a subset of the cases in the Bisschops study, gastric accommodation and gastric hypersensitivity were tested but only a minority had these abnormalities (30% and 23%, respectively, consistent with other published literature).8 Hence, it is not established 1487


Commentary that gastric motor and sensory perturbations are central to the pathogenesis, and, furthermore, even if they are relevant, alone or in combination, the underlying neuropathology and causes of the abnormalities remain largely obscure. In the future, obtaining full-thickness gastric biopsy specimens in patients with FD may become clinically feasible and provide some answers.17 On the other hand, abnormalities of duodenal rather than gastric function may be more important in the pathogenesis of meal-related symptoms. Acid infusion into the duodenum can alter small bowel motility,18 precipitate symptoms such as nausea that may be partially reversed by acid suppression,19 and can induce reflex changes in gastric motor function that mimic the physiology of FD.20 21 Could insults to the upper small bowel be an underlying cause of meal-related FD? A Salmonella outbreak in Spain was documented to lead to a substantial increase in the incidence of dyspepsia (as well as irritable bowel syndrome),22 suggesting that infectious enteritis is a cause of FD. In a tertiary centre, 17% of patients reported possible postinfectious FD23; these cases were more likely to have impaired gastric accommodation which failed to relax after sumatriptan than non-postinfectious cases, suggesting that the damaged reflex nerve pathways may differ in postinfectious FD.23 It is also conceivable that the meal itself is critical in inducing symptoms directly through allergic or non-allergic mechanisms in the small intestine. The importance of food allergy and intolerance, which may in turn induce inflammatory and cytokine responses, has been largely ignored in FD, but might be critically important.24–26 In a nested case–control study from a northern Swedish adult population sample who underwent endoscopy and biopsy, it was observed that there was a subtle increase in duodenal eosinophils in FD cases compared with matched controls27; early satiety was associated with duodenal eosinophilia.27 In paediatric FD, duodenal eosinophilia has also been noted, and symptoms improved after antieosinophil therapy.28 These observations suggest that abnormal duodenal pathology may be relevant in FD and imply that meal-related symptomatology potentially might be blocked by antieosinophil therapy, which would be a major advance. If meal-related symptoms objectively identify most cases with FD, then test meals may have a place in research and clinical practice. Patients, however, may not always notice they have meal-related 1488

complaints; in the Bisschops study, the onset of epigastric pain after the meal was delayed and these patients probably often failed to discern meal-related symptoms.12 Rather than diagnosing FD by exclusion, as is current practice, in patients with a normal upper endoscopy and upper gastrointestinal complaints, a simple standardised meal challenge test may identify those who truly have the condition and, furthermore, help direct medical treatment (eg, to drugs that specifically and favourably alter gastric or duodenal dysfunction). The liquid nutrient drink test (more colloquially called the ‘‘drink and puke’’ test) has already been applied in this fashion.29 There are many versions of this test, but typically subjects are asked to drink a high fat liquid meal at a constant rate (eg, 30 ml/min) until they have unbearable satiety and score their symptoms on a visual analogue scale. Normal controls will develop dyspepsia with this meal challenge, but patients with FD as a group drink significantly lower volumes and have higher symptom scores; normal cut-offs have been defined in the literature,30 31 and the meal has been used to test if drugs can favourably alter the results.32 33 However, based on the Bisschops study,12 it may be preferable to use a solid meal, which might provide better discrimination in the clinic. It is also possible to disguise the food cleverly such that a challenge test meal could theoretically be used to distinguish between those whose symptoms are mainly extraintestinal (or psychologically) based versus those whose symptoms arise from true gastroduodenal perturbations.34 Optimal solid challenge test meals now need to be developed and validated. FD has been an enigma, but there are now tantalising hints that a positive diagnosis is possible, and we will be able to target the pathogenesis more explicitly with particular therapies. Based on the data from Bisschops et al, it seems reasonable to conclude that FD is a meal-related upper abdominal syndrome; minimal symptoms after a test meal might lead one to question the diagnosis.12 The presence of symptoms that are clearly minimal to meals in the upper abdominal region may plainly distinguish FD from GORD or epigastric pain due to other pathological processes. The field is moving forward away from overlapping selfreport symptom-based criteria that arguably have been difficult to apply, and we should all applaud the progress.

REFERENCES

Competing interests: None.

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6. 7. 8.

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15.

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17.

18.

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Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466–79. Talley NJ, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders: a working team report for the Rome II consensus on functional gastrointestinal disorders. Gut 1999;45(Suppl 2):II37–42. Talley NJ, Colin-Jones D, Koch KL. Functional dyspepsia: a classification with guidelines for diagnosis and management. Gastroenterol Int 1991;4:145–60. Ford AC, Moayyedi P. Current guidelines for dyspepsia management. Dig Dis 2008;26:225–30. Talley NJ, Ruff K, Jiang X, et al. The Rome III classification of dyspepsia: will it help research? Dig Dis 2008;26:203–9. Thompson WG. Nonulcer dyspepsia. Can Med Assoc J 1984;130:565–9. Rhind JA, Watson L. Gall stone dyspepsia. Br Med J 1968;1:32. Talley NJ, Vakil N, Moayyedi P. AGA technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756–80. Haag S, Senf W, Hauser W, et al. Impairment of health-related quality of life in functional dyspepsia and chronic liver disease: the influence of depression and anxiety. Aliment Pharmacol Ther 2008;27:561–71. Thomson AB, Barkun AN, Armstrong D, et al. The prevalence of clinically significant endoscopic findings in primary care patients with uninvestigated dyspepsia: the Canadian Adult Dyspepsia Empiric Treatment-Prompt Endoscopy (CADET-PE) study. Aliment Pharmacol Ther 2003;17:1481–91. Talley NJ, Holtmann G, Agreus L, et al. Gastrointestinal symptoms and subjects cluster into distinct upper and lower groupings in the community: a four nations study. Am J Gastroenterol 2000;95:1439–47. Bisschops R, Karamanolis G, Arts J, et al. Relationship between symptoms and ingestion of a meal in functional dyspepsia. Gut 2008;57:1495–1503. Barbera R, Feinle C, Read NW. Abnormal sensitivity to duodenal lipid infusion in patients with functional dyspepsia. Eur J Gastroenterol Hepatol 1995;7:1051–7. Feinle C, D’Amato M, Read NW. Cholecystokinin-A receptors modulate gastric sensory and motor responses to gastric distension and duodenal lipid. Gastroenterology 1996;110:1379–85. Feinle-Bisset C, Vozzo R, Horowitz M, et al. Diet, food intake, and disturbed physiology in the pathogenesis of symptoms in functional dyspepsia. Am J Gastroenterol 2004;99:170–81. Talley NJ, Locke GRI, Lahr BD, et al. Functional dyspepsia, delayed gastric emptying and impaired quality of life. Gut 2006;55:933–9. Rajan E, Gostout CJ, Lurken MS, et al. Endoscopic ‘no hole’ full-thickness biopsy of the stomach to detect myenteric ganglia. Gastrointest Endosc 2008;68:301–7. Samsom M, Verhagen MA, vanBerge Henegouwen GP, et al. Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients. Gastroenterology 1999;116:515–20. Lee KJ, Demarchi B, Demedts I, et al. A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea. Am J Gastroenterol 2004;99:1765–73. Lee KJ, Vos R, Janssens J, et al. Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Liver Physiol 2004;286:G278–84. Simren M, Vos R, Janssens J, et al. Acid infusion enhances duodenal mechanosensitivity in healthy subjects. Am J Physiol Gastrointest Liver Physiol 2003;285:G309–15. Mearin F, Perez-Oliveras M, Perello A, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year followup cohort study. Gastroenterology 2005;129:98–104. Tack J, Demedts I, Dehondt G, et al. Clinical and pathological characteristics of acute-onset functional dyspepsia. Gastroenterology 2002;122:1738–47.

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Commentary 24. 25.

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Walker MM, Talley NJ. Functional gastrointestinal disorders and the potential role of eosinophils. Gastroenterol Clin North Am 2008;37:383–95. Park MI, Camilleri M. Is there a role of food allergy in irritable bowel syndrome and functional dyspepsia? A systematic review. Neurogastroenterol Motil 2006;18:595–607. Zuo XL, Li YQ, Li WJ, et al. Alterations of food antigenspecific serum immunoglobulins G and E antibodies in patients with irritable bowel syndrome and functional dyspepsia. Clin Exp Allergy 2007;37:823–30. Talley NJ, Walker MM, Aro P, et al. Nonulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case–control study. Clin Gastroenterol Hepatol 2007;5:1175–83.

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30.

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Friesen CA, Kearns GL, Andre L, et al. Clinical efficacy and pharmacokinetics of montelukast in dyspeptic children with duodenal eosinophilia. J Pediatr Gastroenterol Nutr 2004;38:343–51. Haag S, Talley NJ, Holtmann G. Symptom patterns in functional dyspepsia and irritable bowel syndrome: relationship to disturbances in gastric emptying and response to a nutrient challenge in consulters and non-consulters. Gut 2004;53:1445–51. Gonenne J, Castillo EJ, Camilleri M, et al. Does the nutrient drink test accurately predict postprandial gastric volume in health and community dyspepsia? Neurogastroenterol Motil 2005;17:44–50. Boeckxstaens GE, Hirsch DP, van den Elzen BD, et al. Impaired drinking capacity in patients with functional

Should computed tomography be the modality of choice for imaging Crohn’s disease in children? The radiation risk perspective David J Brenner Computed tomography (CT) and, more recently, CT enterography are excellent non-invasive tools for diagnosing Crohn’s disease, and for subsequent assessment of the disease, before and after therapy.1 In this light, and given the general availability and ease of use of CT machines, it is not surprising that CT is steadily replacing barium small-bowel followthrough as the radiological modality of choice for imaging Crohn’s disease. There is, however, a potential downside, which is the radiation exposure produced by the CT scan. By their nature, CT scans result in radiation doses which are very much at the high end of those produced in diagnostic radiology, simply because a CT scan is effectively a large number of individual images that are electronically combined to produce a three-dimensional image. The effective dose involved in a CT scan is not large, but it is typically two to six times larger than that from barium small-bowel follow-through. Because of the typical longterm remission/relapse pattern of Crohn’s disease, together with the fact that is predominantly a disease of young people, Crohn’s disease patients are often imaged multiple times which, of course, correspondingly multiplies the radiation dose. Correspondence to: Dr David Brenner, Center for Radiological Research, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA; [email protected] Gut November 2008 Vol 57 No 11

In this light, the report by Desmond et al2 in this issue of the journal (see page 1524) surveying trends in radiation exposure as a result of imaging Crohn’s disease, is most welcome. The study, from Cork University Hospital, Ireland, together with a corresponding report from the US,3 paints a picture of increasing lifetime radiation exposures in Crohn’s disease patients, due almost entirely to the increased use of CT. For example, the Irish study2 estimated that the mean cumulative effective dose per Crohn’s disease patient increased by about a factor of 3 in the past decade. Correspondingly, as reported in the US (Mayo Clinic) study,3 the balance between the numbers of small-bowel followthroughs (SBFRs) and CTs performed to image Crohn’s disease has moved from 90% vs 10% in 2003 in favour of SBFR, to 75% vs 25% in 2007 in favour of CT. Should we be worried about the increased radiation exposure associated with the increased CT usage? After all, while the Irish study reports that mean cumulative radiation doses to Crohn’s disease patients has increases 3-fold in the past decade (from 8 to 25 mSv), this is still not a large radiation dose. An estimate of the age-at-exposure averaged lifetime cancer mortality risk associated with a 25 mSv effective dose is about 1 in 1000, or 0.1%.4–6 One may, of course, ask whether such estimated radiation risks from CT are ‘‘real’’ or simply theoretical extrapolations from much higher-dose scenarios. In fact at

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dyspepsia: relationship with proximal stomach function. Gastroenterology 2001;121:1054–63. Talley NJ, Camilleri M, Chitkara DK, et al. Effects of desipramine and escitalopram on postprandial symptoms induced by the nutrient drink test in healthy volunteers: a randomized, double-blind, placebocontrolled study. Digestion 2005;72:97–103. Choung RS, Cremonini F, Thapa P, et al. The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: a double-blind, randomized, placebo-controlled trial. Neurogastroenterol Motil 2008;20:220–7. Taggart D, Billington BP. Fatty foods and dyspepsia. Lancet 1966;2:465–6.

the average effective dose of 25 mSv2 3 (and certainly at 100 Sv or more, to which 10% of Crohn’s disease patients were exposed2), there are direct epidemiological radiationassociated cancer-risk data7–9 from about 30 000 Japanese atomic-bomb survivors who were several miles away from the epicentres of the explosions at Hiroshima and Nagasaki, and who were exposed to just this same range of low doses as the Crohn’s disease patients. This low-dose group in the two Japanese cities has been followed for more than 50 years, and shows a small but statistically significant increased cancer risk.7–9 Other large-scale epidemiological studies on populations exposed in this dose range have reached the same conclusion.10 Thus, in the context of the CT doses estimated in the Irish study (and the similar doses from the US study), we have direct epidemiological evidence of a small but significant increase in cancer risk due to the radiation exposure, without the need to extrapolate cancer risk estimates from higher doses, with all the attendant uncertainties that entails. An important point that emerges from the Irish study2 relates to children. In particular, patients who were diagnosed with Crohn’s disease in childhood (under 17), were twice as likely as the 17–40-yearold age group to have a high cumulative radiation exposure (.75 mSv), despite the fact that the dose per single CT scan is typically lower in children than in adults.11 12 This issue of paediatric exposure is potentially important because of the increased sensitivity of children to radiation-induced cancer. For example a 10-yearold girl is, on average, about four times more sensitive to radiation-induced cancer than a 50-year-old woman.4 Coupling this with the observation that children with Crohn’s disease are receiving higher cumulative radiation doses than adults with the disease,2 it is clear that the use of CT for imaging Crohn’s disease in children is of some concern. If the age-at-exposure averaged lifetime radiation-related cancer mortality risk were indeed typically 1 in 1000 1489


Commentary for Crohn’s disease patients imaged with CT, the increased cumulative dose, together with the increased radiation sensitivity of a paediatric Crohn’s disease patient, might increase this estimated mortality risk in children to as much as 1 in 300. Given that almost 10% of all Crohn’s disease patients are children,13 such high radiation-associated cancer risks must be of concern. What can be done for these children? Clearly there are alternatives to CT, probably the most promising being magnetic resonance imaging (MRI).14 Until recently, MRI imaging of Crohn’s disease was highly suboptimal, hindered by motion artifacts and lack of appropriate contrast agents. However, in the past few years, the technology has markedly improved,14 15 particularly in the reduction of imaging time, down to only a few seconds. In a 2003 study of contrast-enhanced MRI of the terminal ileum in children with Crohn’s disease, Laghi et al16 correlated their MRI findings with ileal endoscopy and histology, and found a high sensitivity (84%) and specificity (100%) for the detection of Crohn ileitis. Likewise in a subsequent study17 using contrast-enhanced MRI, sensitivity and specificity were both .90% for the detection of Crohn’s disease in the paediatric small bowel. Thus, while further studies are needed, it appears that contrast-enhanced MRI is, or will soon be, a viable option for imaging paediatric Crohn’s disease. Given the

significant potential radiation risks associated with repeated paediatric CTs, MRI should perhaps be considered as a candidate to become the ‘‘first line’’ modality for imaging Crohn’s disease in children. Of course there are also issues associated with MRI cost and availability to consider.14 15 But if we allow that CT remains the firstline modality for imaging adult Crohn’s disease (ideally with reduced radiation doses from those currently delivered18), the necessary resources required to use MRI only for the ,10% of Crohn’s disease patients who are children, may become more feasible.

Correspondence to: Professor Markus W Bu¨chler, Department of Surgery, University of Heidelberg, INF 110, D-69120 Heidelberg, Germany; markus.buechler@ med.uni-heidelberg.de 1490

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REFERENCES 1.

2.

3.

4.

5.

6.

Paulsen SR, Huprich JE, Fletcher JG, et al. CT enterography as a diagnostic tool in evaluating small bowel disorders: review of clinical experience with over 700 cases. Radiographics 2006;26:641–57. Desmond AN, O’Regan K, Curran C, et al. Crohn’s disease: factors associated with exposure to high levels of diagnostic radiation. Gut 2008;57:1524–9. Peloquin JM, Pardi DS, Sandborn WJ, et al. Diagnostic ionizing radiation exposure in a populationbased cohort of patients with inflammatory bowel disease. Am J Gastroenterol 2008;103:1–8. National Research Council. Health risks from exposure to low levels of ionizing radiation – BEIR VII. Washington, DC: The National Academies Press, 2006. Brenner DJ, Hall EJ. Computed tomography – an increasing source of radiation exposure. N Engl J Med 2007;357:2277–84. Hall EJ, Brenner DJ. Cancer risks from diagnostic radiology. Br J Radiol 2008;81:362–78.

Ju¨rgen Weitz, Markus W Bu¨chler

Department of Surgery, University of Heidelberg, Germany

8.

Competing interests: None declared.

Branch intraductal papillary mucinous neoplasms: just the tip of the iceberg? Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have drawn considerable interest in recent years as we begin to learn more about the natural history of this disease. It is now commonly accepted that these tumours can be classified into two main categories according to their origin in the gland— that is main duct IPMN (MD-IPMN) and

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branch duct IPMN (BD-IPMN). It is also well documented that IPMNs may progress through different stages of dysplasia into invasive carcinoma. It is, however, not well known whether all IPMNs ultimately progress into invasive cancer and if so what the timeline of this process is. In contrast to classical ductal adenocarcinomas of the pancreas, however, where patients always present with fully developed carcinoma with a dismal prognosis, many patients with IPMNs present early enough so that an intervention might prevent the development of pancreatic cancer. In fact, about 8–43% of

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Preston DL, Ron E, Tokuoka S, et al. Solid cancer incidence in atomic bomb survivors: 1958–1998. Radiat Res 2007;168:1–64. Pierce DA, Preston DL. Radiation-related cancer risks at low doses among atomic bomb survivors. Radiat Res 2000;154:178–86. Preston DL, Shimizu Y, Pierce DA, et al. Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950–1997. Radiat Res 2003;160:381–407. Cardis E, Vrijheid M, Blettner M, et al. The 15country collaborative study of cancer risk among radiation workers in the nuclear industry: Estimates of radiation-related cancer risks. Radiat Res 2007;167:396–416. Gaca AM, Jaffe TA, Delaney S, et al. Radiation doses from small-bowel follow-through and abdomen/pelvis MDCT in pediatric Crohn disease. Pediatr Radiol 2008;38:285–91. Jaffe TA, Gaca AM, Delaney S, et al. Radiation doses from small-bowel follow-through and abdominopelvic MDCT in Crohn’s disease. AJR Am J Roentgenol 2007;189:1015–22. Gunesh S, Thomas GA, Williams GT, et al. The incidence of Crohn’s disease in Cardiff over the last 75 years: an update for 1996–2005. Aliment Pharmacol Ther 2008;27:211–9. Toma P, Granata C, Magnano G, et al. CT and MRI of paediatric Crohn disease. Pediatr Radiol 2007;37:1083–92. Lin MF, Narra V. Developing role of magnetic resonance imaging in Crohn’s disease. Curr Opin Gastroenterol 2008;24:135–40. Laghi A, Borrelli O, Paolantonio P, et al. Contrast enhanced magnetic resonance imaging of the terminal ileum in children with Crohn’s disease. Gut 2003;52:393–7. Darbari A, Sena L, Argani P, et al. Gadoliniumenhanced magnetic resonance imaging: a useful radiological tool in diagnosing pediatric IBD. Inflamm Bowel Dis 2004;10:67–72. McCollough CH, Bruesewitz MR, Kofler JM Jr. CT dose reduction and dose management tools: overview of available options. Radiographics 2006;26:503–12.

patients with MD-IPMNs and 54–94% of patients with BD-IPMNs present with non-malignant lesions.1 Whereas it is well accepted that patients with MD-IPMN should undergo resection of the lesion at the time of diagnosis, current guidelines recommend non-surgical management of a certain subgroup of BD-IPMNs.1 Asymptomatic patients with tumours ,30 mm in size without mural nodules and without a main duct dilation (.6 mm) fall into this category. Of note, these recommendations were not based on long-term follow-up of such patients but on the extremely low incidence of invasive cancer of patients initially presenting with these features. Recently, follow-up studies regarding this issue have been published. Salvia et al followed 89 patients with low-risk BD-IPMNs over a median of 32 months; surgery was performed in only 5 of these patients due to an increase in size, and none of the surgical specimens demonstrated malignancy.2 Tanno et al included 82 patients with low-risk BD-IPMNs in a similar Gut November 2008 Vol 57 No 11


Commentary protocol with a median follow-up of 61 months. The vast majority of tumours (84.1%) remained unchanged over time. In 9 patients, the tumours enlarged and in 4 patients nodules developed. Only 7 of these patients underwent resection of their tumours; again, none of the specimens demonstrated signs of malignancy.3 Based on these studies, the above-mentioned guidelines seem to be well justified. The study of Uehara et al published in this issue of Gut (see page 1561), however, adds another layer of complexity to the issue of management of BD-IPMNs.4 The authors included 60 patients with BD-IPMNs with a main duct size of ,10 mm and a negative cytology of the pancreatic juice and followed them over a mean of 87 months. Therefore, this is the study with the longest follow-up published so far. Pancreatic cancer developed in 7 patients (12%) during follow-up. Of note, five of these cancers were ductal adenocarcinomas that developed separate from the index lesion after 18–112 months of follow-up. The authors calculated the incidence of development of ductal adenocarcinoma to be 1.1% per year, which was a 26-fold increase compared with a control group. The only risk factor for development of malignant disease the authors could identify was age .70 years. What is particularly disturbing when analysing these results is, that—according to the given data in the manuscript—all five ducal adenocarcinomas developed in a different region of the pancreas from the BD-IPMN. Presumably, none of these cancers could have been prevented by limited surgery of the BD-IPMN at the time of diagnosis. One can certainly question the inclusion of some BD-IPMNs larger than 3 cm in the study; one might also want to discuss the fact that most patients were followed by ultrasonography rather than CT or MRI. Another potential point of concern is the quality of the initial imaging ruling out pre-existing malignant pancreatic lesions. More interesting, however, is the question regarding the biological meaning of the results presented by the authors. A higher incidence of extrapancreatic cancers (stomach, colon, rectum, lung, breast and liver) in patients with IPMNs has been well described in the literature, with an incidence of 10–29%.1 5 In addition, the occurrence of synchronous or metachronous ductal adenocarcinoma of the pancreas was described in 9.2% of 76 patients with IPMNs.6 Interestingly, all these IPMNs were BD-IPMNs with a


mean diameter of 3 cm. The reasons for these associations are unclear; they might be explained by underlying genetic abnormalities or by exposure to an external carcinogen. One should also keep in mind that BD-IPMNs are well known to be multifocal in up to 64% of patients, which might be the origin of malignant development in the pancreas.2 Although the authors reported the five cancers to be ductal adenocarcinomas, the histopathological differentiation between ductal adenocarcinomas and malignant IPMNs may occasionally be difficult.7 The authors did not perform molecular analyses in order to characterise the malignant tumours further; several molecular changes characterising ductal adenocarcinoma and malignant IPMNs have been described in the literature.7 It would have also been extremely interesting if the authors had performed molecular analyses of the apparently normal pancreatic tissue, in order to search for underlying molecular changes. In light of the presented data one should also pose a question regarding the safety of the current guidelines recommending surveillance of ‘‘low-risk’’ BDIPMNs. Even though these guidelines have been strengthened by the two above-cited prospective studies and the low recurrence rates in the pancreatic remnant after resection of non-malignant BD-IPMNs, other studies demonstrated that the definition of ‘‘low-risk’’ BDIPMN chosen in the guidelines might be debatable.8–10 Development of a pancreatic cancer with its dismal prognosis should be avoided at all costs. In light of development of relatively advanced cancer distant to the index lesions in the study of Uehara et al,4 one might argue that a more liberal indication for surgical exploration with a careful examination of the pancreas, including intraoperative ultrasound, might have detected some of the cancers (or premalignant lesions) earlier during surgery in the reported patients. Despite the fact that the published guidelines seem to be based on the best available data and therefore seem to be well justified, further reports providing more data regarding the natural history as well as molecular changes of the index lesion and the unaffected pancreas are very important. A better understanding of these molecular changes might help to better judge the individual risk of the patient. Clearly, some BD-IPMNs have the potential eventually to become malignant even though the magnitude of this

risk as well as the timeline need to be better defined. Of even greater importance, however, are the findings of the authors that in the presence of BD-IPMN there seems to be a state of cancerogenesis within the pancreas that might put the patient at a higher risk for development of ductal adenocarcinoma. If this new finding holds true in the future, then we have to rethink completely the role and importance of such BD-IPMNs. In the future, BD-IPMNs might be seen as indicator lesions (tip of the iceberg) that guide our cancer preventive measures that for the moment can only be surgery. BD-IPMNs should therefore become a very attractive pancreatic cancer research model in humans. These data will help to refine the guidelines regarding the management of patients with BD-IPMNs and to individualise the patient care in order to avoid unnecessary surgery, but also to avoid the development of pancreatic cancer during surveillance of the affected patient. Competing interests: None. Gut 2008;57:1490–1491. doi:10.1136/gut.2008.156380

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17–32. Salvia R, Crippa S, Falconi M, et al. Branch-duct intraductal papillary mucinous neoplasms of the pancreas: to operate or not to operate? Gut 2007;56:1086–90. Tanno S, Nakano Y, Nishikawa T, et al. Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results. Gut 2008;57:339–43. Uehara H, Nakaizumi A, Ishikawa O, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut 2008;57:1561–5. Riall TS, Stager VM, Nealon WH, et al. Incidence of additional primary cancers in patients with invasive intraductal papillary mucinous neoplasms and sporadic pancreatic adenocarcinomas. J Am Coll Surg 2007;204:803–13. Yamaguchi K, Ohuchida J, Ohtsuka T, et al. Intraductal papillary-mucinous tumor of the pancreas concomitant with ductal carcinoma of the pancreas. Pancreatology 2002;2:484–90. Hingorani SR. Location, location, location: precursors and prognoses for pancreatic cancer. Gastroenterology 2007;133:345–50. Schmidt CM, White PB, Waters JA, et al. Intraductal papillary mucinous neoplasms: predictors of malignant and invasive pathology. Ann Surg 2007;246:644–51. Jang JY, Kim SW, Lee SE, et al. Treatment guidelines for branch duct type intraductal papillary mucinous neoplasms of the pancreas: when can we operate or observe? Ann Surg Oncol 2008;15:199–205. Nagai K, Doi R, Kida A, et al. Intraductal papillary mucinous neoplasms of the pancreas: clinicopathologic characteristics and long-term followup after resection. World J Surg 2008;32:271–8.

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Commentary

Prevention of post-ERCP pancreatitis: a little antacid might go a long way Anil B Nagar, Fred Gorelick A major procedural complication in gastroenterology is post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis. This occurs in 4–10% of patients undergoing ERCP. While the severity of post-ERCP pancreatitis is generally mild, up to 10% of cases may be severe and complicated by necrosis, multi-organ failure and even death.1 Prevention of this complication has proven only partially successful with patient selection and procedural measures contributing significantly to decreases in this complication. Although many pharmacological interventions have been used, few have demonstrated consistent or substantial benefits.1 A possible exception may be non-steroidal anti-inflammatory agents.2 In this issue of the journal, Noble and co-workers3 (see page 1566) surprisingly identify the pH of the contrast media used to opacify the pancreatic duct as a potential factor in post-ERCP pancreatitis. Certain manipulations increase the risk of developing post-ERCP pancreatitis. These include sphincter of Oddi dysfunction, repeated attempts at cannulation, repeated contrast injection, and papillotomy. Each of these interventions can result in increased pressure within the pancreatic duct. Thus, the empirical use of temporary pancreatic duct stents to reduce intraductal pressure and prevent post-ERCP pancreatitis began about 15 years ago. The literature has consistently supported their use, particularly in reducing severe pancreatitis.4 The contributory role of contrast agents in post-ERCP pancreatitis has been explored. Osmolality was thought to be a causative factor, but the use of low osmolality contrast agents has not resulted in a lower incidence of post-ERCP pancreatitis.5 In this issue, Noble and co-workers VA Healthcare CT and Yale University School of Medicine, West Haven, Connecticut, USA Correspondence to: Dr Fred Gorelick, VA Connecticut Healthcare System, Yale University, Building 4, 950 Campbell Ave, West Haven, CT 06516, USA; [email protected] 1492

explore a previously unexamined property of contrast media, its pH. Noble describes a potentially important response to the contrast media used to opacify the pancreatic duct using a rat model of post-ERCP pancreatitis. In their studies, acute pancreatitis occurs when contrast media, which is usually mildly acidic, is injected under pressure into the rat pancreatic duct. Notably, the features of pancreatitis varied when the pH of the contrast media was adjusted with HEPES buffer (4-(2-hydroxyethyl)piperazine-1ethanesulfonic acid). Thus, when the contrast had a pH of 7.3, there was little pancreatitis. However, progressively worse disease was produced when the pH was reduced to 6.9 and 6.0. The injection of an acid solution (phosphatebuffered saline, pH 6.9) into the pancreatic duct did not result in pancreatitis. Thus, in addition to an acidic pH, other properties of contrast media, such as hypertonicity and hydrostatic pressure, might act in concert with media acidification to cause pancreatitis. The investigators next examined the mechanism of the injury. Neural pathways, especially those mediated through substance P and its receptor, neurokinin 1 (NK1), have been shown to modulate the inflammatory response in acute pancreatitis.6 Such inflammation is described as neurogenic. Notably, a previous study demonstrated that blockade of the substance P receptor reduces post-ERCP pancreatitis.7 This response appeared to be due to activation of pathways on pancreatic sensory nerves. Noting that the transient receptor potential vanilloid 1 (TRPV1) receptor is found on sensory nerves and can be activated by acid, Noble and colleagues investigated its role in their model. The addition of resiniferatoxin, a selective TRPV1 antagonist, reduced the severity of pancreatitis in response to an acidic contrast media. This finding implicates TRPV1 activation in response to acidic contrast media as a determinant of pancreatitis severity. Interestingly, TRV1 has also been implicated in the mediation of pain in acute and chronic pancreatitis.8 9

Since other ion channels and signalling pathways can be activated by acid and resiniferatoxin can affect other neural responses, additional studies would be needed to be certain the responses observed by Noble and colleagues were due to TRPV1 alone.10 Indeed, the potential importance of other neural pathways is underscored by the fact that chemical inhibition, but not genetic deletion of TRPV1, resulted in an inhibition of neurogenic inflammation in a mouse model of caerulein-induced pancreatitis.11 Changes in the extracellular pH can be sensed by a number of plasma membrane proteins, including TRPV1 and acid-sensing ion channels (ASICs), which transduce signals into cell.10 Many of the acid-sensing proteins are found on plasma membrane of nerves. Other proteins can sense changes in cytosolic pH. For example, the catalytic activity of the intracellular protein kinase, Pky2, is stimulated by acid.12 There is a growing recognition that an acute change in pH can affect many physiologic and pathologic responses. In the context of acute pancreatitis, one of the most important is the stimulation of inflammation.13 As shown in fig 1, acid can stimulate inflammation by several mechanisms. Noble suggests that in the post-ERCP model, this occurs by direct stimulation of sensory nerves that leads to neurogenic inflammation. However, an acidic challenge can also directly sensitise macrophages to the lipopolysacchride (LPS)-dependent generation of inflammatory mediators such as tumour necrosis factor a (TNFa) and interleukin 6 (IL6).13 Notably, both TNFa and IL6 mediate injury in acute pancreatitis. Not all biological acids elicit the same cellular responses. Thus, hydrochloric acid tends to cause a greater inflammatory response than lactic acid in stimulated LPS macrophages.13 An acidic pH can also affect epithelial cell function. For example, it has been shown to increase paracellular permeability.14 Such a response would allow the contents of the pancreatic duct lumen to reach the interstitial space. Finally, preliminary studies from our laboratory suggest that an acidic pH can be a sensitiser to cholecystokinin-induced injury in the pancreatic acinar cell (unpublished data). In summary, in addition to stimulation of neural pathways linked to inflammation, other acid-sensitive mechanisms that may also contribute to contrast-induced pancreatitis. The notion that neurogenic inflammation has an important role in the pathogenesis of post-ERCP pancreatitis Gut November 2008 Vol 57 No 11


Commentary

Figure 1 An acidic pH may have multiple effects that are relevant to the pathogenesis of acute pancreatitis. The study by Noble et al3 emphasises the direct effect of a low pH contrast media on nerves that subsequently stimulate neurogenic inflammation (as indicated by the solid arrows). However, as indicated by the dashed arrows, an acid challenge may have damaging effects that are independent of nerves. These include direct pro-inflammatory effects such as stimulation of inflammatory responses by macrophages. An acid challenge may also directly affect epithelial function and sensitise acinar cells to injury. Finally, an acid challenge may also enhance the pain responses of pancreatitis. is important. It may be relevant that receptors on sensory neurons linked to pain and inflammation can be activated by not only acid, some are also pressure and heat sensitive. Thus, the pressure exerted by the force of contrast injection and the thermal effects of a papillotomy may also be important in disease pathogenesis. In this context, activation by TRPV1 usually requires a pH of less than 6.0, a value lower than that needed to cause pancreatitis in Noble’s study and lower than that found in contrast media. However, mildly acidic conditions (pH 6–7) can sensitise the TRV1 to other activated stimuli, such as heat.15 This relationship might account for the dramatic effects of a mildly acidic contrast media in the study by Noble and co-workers. It is possible that synergy


between acid, pressure, tonicity, and heat might all affect the pancreatitis response and neurogenic inflammation. Thus, there may be benefits beyond just raising the pH of the buffer if neurogenic inflammation could be directly blocked. An important issue is whether these observations should affect clinical practice. Although ERCP contrast dye is buffered, the pH ranges are broad among commonly used media include Renografin-60 (Bracco Diagnostics, Princton, NJ, USA) pH of 6.0–7.7 and Omnipaque 240 (Amersham Health, Oslo, Norway) pH 6.8–7.7. Indeed, the variability in contrast pH along with other dissimilarities in the composition of contrast media, could account for some of the differences in the rates of post-ERCP pancreatitis reported among institutions. The findings by Noble and colleagues are compelling. If the protective effects of buffering contrast are as dramatic in humans as now shown in rats, a randomised clinical study comparing an acidic versus a neutral pH contrast media could resolve this issue. However, due to the low incidence of post-ERCP pancreatitis and routine use of pancreatic duct stents in high-risk patients, such a study would require large numbers of patients and should be best approached as a multicentre investigation. It would also require careful documentation of the type of contrast media, its pH at the time of injection, and a standardised buffering protocol. Such a study would probably best be undertaken in collaboration with the makers of contrast media used for ERCP. Acknowledgements: The authors thank Dr C Chung for critically reviewing this manuscript and for his many helpful suggestions.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Funding: Research grants DK54021 and a Veterans Administration Merit Award to FG. Competing interests: None. Gut 2008;57:1492–1493. doi:10.1136/gut.2008.157289

15.

Frank CD, Adler DG. Post-ERCP pancreatitis and its prevention. Nat Clin Pract Gastroenterol Hepatol 2006;3:680–8. Elmunzer BJ, Waljee AK, Elta GH, et al. A metaanalysis of NSAIDs in the prevention of post-ERCP pancreatitis. Gut 2008;57:1262–7. Noble MD, Romac J, Vigna SR, Liddle RA. A pHsensitive neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis. Gut 2008;57:1566–71. Singh P, Das A, Isenberg G, et al. Does prophylactic pancreatic stent placement reduce the risk of postERCP acute pancreatitis? A meta-analysis of controlled trials. Gastrointest Endosc 2004;60:544–50. George S, Kulkarni AA, Stevens G, et al. Role of osmolality of contrast media in the development of post-ERCP pancreatitis: a metanalysis. Dig Dis Sci 2004;49:503–8. Bhatia M, Saluja AK, Hofbauer B, et al. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Physiology 1998;95:4760–5. He ZJ, Winston JH, Yusuf TE, et al. Intraductal administration of an NK1 receptor antagonist attenuates the inflammatory response to retrograde infusion of radiological contrast in rats: implications for the pathogenesis and prevention of ERCP-induced pancreatitis. Pancreas 2003;27:e13–7. Wick EC, Hoge SG, Grahn SW, et al. Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2006;290:G959–69. Xu GY, Shenoy M, Winston JH, et al. P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut 2008;57:1230–7. Holzer P. Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 2007;292:G699–705. Romac JM, McCall SJ, Humphrey JE, et al. Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis. Pancreas 2008;36:394–401. Preisig PA. The acid-activated signaling pathway: starting with Pyk2 and ending with increased NHE3 activity. Kidney Int 2007;72:1324–9. Kellum JA, Song M, Li J. Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Crit Care 2004;8:331–6. Menconi MJ, Salzman AL, Unno N, et al. Acidosis induces hyperpermeability in Caco-2BBe cultured intestinal epithelial monolayers. Am J Physiol 1997;272:G1007–21. Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple painproducing stimuli. Neuron 1998;21:531–43.

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Subdividing functional dyspepsia: a paradigm shift? Nicholas J Talley Gut 2008 57: 1487-1489

doi: 10.1136/gut.2008.155788

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