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the incidence and natural course of portal vein thrombosis (PVT) in viral cirrhosis. Despite the interest of the study being the third to report incidence of PVT in cirrhotics, it presents several inconsistencies and drawbacks in design and data analysis. First, reported incidence of PVT included six patients with only splenic vein thrombosis, thus being 36/150, 24%. Moreover, the occurrence of PVT is strangely not equally distributed during the follow-up, with a 12.8% incidence in the first years and about 2% per year during the followup. This is in contrast with the current knowledge of a greater prevalence of PVT in patients with more advanced liver disease. Second, patients were recruited for the study during 11 years, and it is stated that Doppler ultrasonography (US) were performed at least every 6–12 months. However, surprisingly, the median number of US per patient was only 4.4, leading to a period of time covered of a maximum of 4 years. Third, correlation of flows at US Doppler at inclusion with occurrence of PVT after years from the initial evaluation is unlikely due to changing hemodynamics in cirrhotic patients overtime. Fourth, it is difficult to understand why patients were tested for prothrombotic disorders at the beginning of the enrollment in the study (in year 1998 the potential role of these alterations in cirrhosis was still not defined). Fifth, US is characterized by diagnostic limitations, especially in extra-hepatic segments of PV or other splanchnic veins. Sixth, worsening of PVT has been described in only 1/23 patients, data very different from previous studies that described progression of PVT in 48–75% of cases at 2 years (2,3). Finally, the way that data on PVT and survival was analyzed does not allow to conclude that PVT does not have an impact on survival. Kaplan–Meyer curve of survival is faulty because the number of patients plotted in the figure is 156 and not 150, and survival was considered from the enrollment in the study. Therefore, for example a patient developing PVT after 7 years of follow-up and dying 1 month after it is considered as being alive for 7 years and 1 month. In conclusion, we believe that the interpretation of the described data is difficult and no recommendations can be drawn The American Journal of GASTROENTEROLOGY

according to the results of the present manuscript. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Maruyama H, Okugawa H, Takahashi M et al. De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes. Am J Gastroenterol 2013;108:568–74. 2. Luca A, Caruso S, Milazzo M et al. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology 2012;265:124–32. 3. Senzolo M, M Sartori T, Rossetto V et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int 2012;32:919–27. 1

Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, Padua University Hospital, Padua, Italy; 2 Hepatic Hemodynamic Laboratory, Liver Unit, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), CIBERehd, University of Barcelona, The Hospital Clínic, Barcelona, Spain. Correspondence: Marco Senzolo, MD, PhD, Multivisceral Transplant Unit, Department of Surgical Oncological and Gastroenterological Sciences, University Hospital of Padua, Via Giustiniani 2, 35128 Padua, Italy. E-mail: [email protected]

Response to Senzolo and García-Pagán Hitoshi Maruyama, MD, PhD1 doi:10.1038/ajg.2013.298

To the Editor: We appreciate the interest of Senzolo and García-Pagán (1) in our recent work. The study was properly performed and the data were correctly analyzed, though the total number of patients with portal vein thrombosis in figure 3 (n = 48) was typing error (It should be 42). Most of your comments depend on the characteristics of the cohort and study design based on retrospective setting. In fact, the distribution and detectability of thrombus might be influenced by the diagnostic performance of imaging tool, and it may not be always easy to detect thrombus in the extrahepatic portal vein

by Doppler ultrasonography. However, the study was done consistently throughout the study period by the experienced physician. Relatively stable and less progressive condition was a typical course of portal vein thrombosis. Although we understand some of the data are not consistent with your previous works, it cannot be denied the possibility of heterogeneity in the natural course of portal vein thrombosis. Nonetheless, we acknowledge the limitations of our retrospective study. The data need to be validated in the study with prospective setting. CONFLICT OF INTEREST

The author declares no conflict of interest. REFERENCE 1. Senzolo M, García-Pagán JC. Incidence and natural course of portal vein thrombosis in cirrhosis. Am J Gastroenterol 2013;108:1807–8 (this issue). 1

Department of Gastroenterology, Chiba University Graduate School of Medicine, Chiba, Japan. Correspondence: Hitoshi Maruyama, MD, PhD, Department of Gastroenterology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba 260-8670, Japan. E-mail: [email protected]

Overlap Between Postprandial Distress Syndrome and Epigastric Pain Syndrome in The DIAMOND Study Jan Tack, MD, PhD1 and Florencia Carbone, MSc2 doi:10.1038/ajg.2013.295

To the Editor: We read with interest the report in the April 2013 issue of the American Journal of Gastroenterology on the symptom overlap between postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) of the Rome III functional dyspepsia (FD) classification (1). In this paper, Vakil and colleagues used the database of the Diamond VOLUME 108 | NOVEMBER 2013 www.amjgastro.com


study (NCT00291746) to assess the validity of the Rome III criteria and PDS/EPD subgrouping in patients with upper gastrointestinal symptoms and no gastroesophageal reflux disease (GERD). According to the Rome III consensus, FD is defined as the presence of early satiation, postprandial fullness, epigastric pain, and epigastric burning, in the absence of organic, systemic, or metabolic disease that is likely to explain the symptoms. In addition, the Rome III consensus proposed to distinguish the postprandial distress syndrome (PDS; meal-related dyspeptic symptoms, characterized by postprandial fullness and early satiation) from the epigastric pain syndrome (EPS; mealunrelated dyspeptic symptoms, characterized by epigastric pain and epigastric burning) (2). The Diamond study consists of a large database of 336 patients with upper gastrointestinal symptoms and used state-of-the-art techniques (endoscopy, esophageal pH monitoring) to diagnose GERD (3). The authors identified 138 patients with FD based on negative endoscopy and negative reflux evaluation. Of these, only 13 had PDS alone (10%), 31 had EPS alone (24%) and overlapping PDS/EPS was present in 86 patients (66%). Based on the major overlap between EPS and PDS, the authors question the value of subdividing FD into EPS and PDS. The paper by Vakil et al. (1) is not the first study to report considerable overlap between EPS and PDS in patient samples (4). In support of the Rome III subdivision, three large population-based studies found excellent and significant separation between EPS and PDS in community samples from North America, Scandinavia, and Italy (4–7). On the other hand, studies in patient samples reported considerable overlap of EPS and PDS, in up to 55% of the subjects (4). Factors contributing to the overlap in patient samples may include the relatively low frequency and severity thresholds set in the Rome III diagnostic questionnaires for EPS and PDS, and linguistic and cultural differences in separating painful symptoms (EPS) from non-painful symptoms (PDS). In addition, although conceptually the Rome III subdivision refers to PDS as meal-related © 2013 by the American College of Gastroenterology

dyspeptic symptoms and EPS as mealunrelated symptoms, the relationship of symptoms to meal is currently not used in the diagnostic questionnaire. Previous studies have shown that evaluation of the relationship of symptoms to meal ingestion is able to generate a complete separation of two subgroups (8). The overlap reported in the analysis of the Diamond study, however, is larger than in any of the previous studies, and the proportion of EPS patients is also larger than in any of the previous studies (1,4). When interpreting these unusual results, a number of important limitations should be considered. First of all, as the Diamond study preceded the publication of the Rome III criteria, the subdivision into EPS and PDS was not based on a Rome III diagnostic criteria, but used post-hoc interpretations of a gastrointestinal symptom rating scale (GSRS)-based 19 item questionnaire to assess upper gastrointestinal symptoms. The recall of the questionnaire, limited to 1 week, is not in line with the Rome definitions and questionnaire, which use a longer time frame. The details of the non-GERD symptoms questionnaire used in the Diamond study are not provided, but it seems less likely that these closely match the detail of the Rome questionnaire, which for instance for epigastric pain is a 9-question module. As different “diagnostic” questionnaires are likely to generate different results and prevalences, some of the differences between this and previous studies may be attributable to the questionnaire used. A second important limitation is the focus of the Diamond study on GERD. Although the study aimed at including patients with presumed upper gastrointestinal symptoms, with the use of the Reflux Disease Questionnaire and study-related additional investigations including endoscopy and pH monitoring, it is clear that reflux disease was the true focus of this study. In a previous FD cohort study, epigastric pain and epigastric burning were more frequently found in patients with pathological esophageal pH monitoring (9), indicating that these (EPS) symptoms may overlap with GERD. This probably explains why EPS was the largest subgroup in the Diamond study, whereas all other studies

in the general population and in patient samples of FD found a higher prevalence of PDS (4). The Rome III subdivision into EPS and PDS remains the current standard for research and drug development in FD. Its validity is supported by the available epidemiological data, and by therapeutic efficacy for specific drugs that seems to be limited to one of both FD subgroups (4,10,11). Nevertheless, further fine-tuning is clearly needed, considering the known overlap between both entities. The study by Vakil et al. (1) confirms this overlap, but the unusual size of the overlap and the EPS dominance probably reflect the refluxfocused setting of the study and the limitations of the questionnaires used to post-hoc identify PDS and EPS. Meanwhile, Rome IV is being prepared, and the Rome IV committee on functional gastroduodenal disorders will decide whether the PDS/EPS subdivision deserves moving forward or needs to be abandoned. CONFLICT OF INTEREST

The authors declare no conflict of interest. REFERENCES 1. Vakil N, Halling K, Ohlsson L et al. Symptom overlap between postprandial distress and epigastric pain syndromes of the Rome III dyspepsia classification. Am J Gastroenterol 2013;108:767–74. 2. Tack J, Talley NJ, Camilleri M et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466–79. 3. Dent J, Vakil N, Jones R et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut 2010;59: 714–21. 4. Tack J, Talley NJ. Functional dyspepsia— symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol 2013;10:134–41. 5. Choung RS, Locke GR, Schleck CD et al. Do distinct dyspepsia subgroups exist in the community? A population-based study. Am J Gastroenterol 2007;102:1983–9. 6. Aro P, Talley NJ, Ronkainen J et al. Anxiety is associated with uninvestigated and functional dyspepsia III (ROME criteria) in a Swedish population based study. Gastroenterology 2009;137:94–100. 7. Zagari RM, Law GR, Fuccio L et al. Epidemiology of functional dyspepsia and subgroups in the Italian general population: an endoscopic study. Gastroenterology 2010;138:1302–11. 8. Bisschops R, Karamanolis G, Arts J et al. Relationship between symptoms and ingestion of a meal in functional dyspepsia. Gut 2008;57: 1495–503.

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9. Tack J, Caenepeel P, Arts J et al. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Gut 2005;54:1370–6. 10. Altan E, Masaoka T, Farré R et al. Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome. Expert Rev Gastroenterol Hepatol 2012;6:533–44. 11. Locke GR, Bouras EP, Howden CW et al. The Functional Dyspepsia Treatment Trial (Fdtt) key results. Gastroenterology 2013;144 (Suppl 1): S-140 (abstract). 1 University Leuven—Gastroenterology, Leuven, Belgium; 2University of Leuven—TARGID, Leuven, Belgium. Correspondence: Jan Tack, MD, PhD, University Leuven—Gastroenterology, Herestraat 49, Leuven 3000, Belgium. E-mail: [email protected]

Response to Tack and Carbone Nimish Vakil, MD, FACG, AGAF, FASGE, FACP1 and Börje Wernersson, BSc2 doi:10.1038/ajg.2013.299

To the Editor: Dyspepsia is a common problem in primary care accounting for approximately 10% of all outpatient office visits. Despite this, there is no effective therapy and no approved drugs in the Western world for this disorder. In part, the problem is related to the definition of dyspepsia, which has confounded regulatory authorities and investigators. The Rome III definition of functional dyspepsia and its sub-classification into epigastric pain syndrome and post-prandial distress syndrome overlaps with other disorders of importance. Wang et al. (1) studied 3,014 patients presenting to a specialty clinic and found that 25% of patients with functional dyspepsia met the criteria for irritable bowel syndrome and 31% of patients with irritable bowel syndrome met criteria for functional dyspepsia. In total, 24% of the patients with functional dyspepsia met the criteria of both the epigastric pain syndrome and post-prandial distress syndrome. In another study, epigastric pain syndrome and post-prandial syndrome overlapped in 50% of patients with functional dyspepsia, numbers that are very similar to those reported in our study (2). Our The American Journal of GASTROENTEROLOGY

study, which was performed in a clinically relevant population (primary care consulters with upper gastrointestinal symptoms), demonstrates the extensive overlap of dyspepsia with reflux disease. Our study also demonstrates that epigastric pain syndrome and post-prandial distress syndrome can be identified in many patients with gastroesophageal reflux disease (GERD) (3). The original Rome III document recommended the use of the epigastric pain syndrome and post-prandial distress syndrome for pathophysiological studies and therapeutic research (4). Ochi et al. (5) studied gastric reservoir function, autonomic nervous function, and endoscopic findings in patients with functional dyspepsia and found no pathophysiological differences between patients with postprandial distress syndrome and epigastric pain syndrome, suggesting the absence of a specific pathophysiologic mechanism for these syndromes. Researchers performing therapeutic studies are faced with the challenge of separating functional dyspepsia from irritable bowel syndrome (IBS) and GERD and dealing with the overlap of epigastric pain syndrome and post-prandial distress syndrome. Regulatory guidelines for symptomatic syndromes call for a conceptual framework and a patient-reported outcome instrument that provides a valid measure of the patient’s symptom experience before and after any putative therapy in a unique disorder or syndrome (6). Currently, we are unable to separate functional dyspepsia from other relevant disorders by the criteria we have created. The subgroups of functional dyspepsia (epigastric pain syndrome and post-prandial distress syndrome) show considerable overlap with each other and are also identified in reflux disease and IBS, suggesting the lack of a unique underlying pathophysiology for each of these syndromes. These facts make the development of a patient-reported outcome document that meets regulatory requirements impossible. There are limitations with our study and with others that have addressed this subject, but many of the same criticisms may be applied to the studies cited to support the breakdown of functional dyspepsia

into epigastric pain syndrome and postprandial distress syndrome. The overriding message from all these data is that a new conceptual framework is required for the definition and classification of functional dyspepsia if we are to make progress in helping our patients with this common and distressing problem. We appreciate Tack and Carbone’s interest in our paper (7). CONFLICT OF INTEREST

Nimish Vakil has received consultancy fees from AstraZeneca, Ironwood Pharmaceuticals, Takeda Pharmaceutical, and XenoPort, and has ownership interest (e.g. stocks, stock options) in Meridian Bioscience. Borje Wernersson is employed by Astra Zeneca. REFERENCES 1. Wang A, Liao X, Xiong L et al. The clinical overlap between functional dyspepsia and irrirable bowel syndrome based on Rome III criteria. BMC Gastroenterol 2008; http://www. biomedcentral.com/1471-230X/8/43, accessed 27/6/2013. 2. Nwokediuko S, Ijoma U, Obienu O. Functional dyspepsia: subtypes, risk factors and overlap with irritable bowel syndrome in a population of African patients. Gastroenterol Res Pract 2012;2012:562393 doi: 10.1155/2012/562393. e-pub ahead of print 19 November 2012, accessed 27/6/2013. 3. Vakil N, Halling K, Ohlsson L et al. Symptom overlap between postprandial distress and epigastric pain syndromes of the Rome III dyspepsia classification. Am J Gastroenterol 2013;108:767–74. 4. Tack J, Talley N, Camilleri M et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466–79. 5. Ochi M, Tominaga K, Tanaka F et al. Clinical classification of subgroups according to the Rome III criteria cannot be used to distinguish the associated respective pathophysiology in Japanese patients with functional dyspepsia. Intern Med 2013;52:1289–93. 6. Anonymous. Guidance for Industry PatientReported Outcome Measures: Use in Medical Product Development to Support Labeling Claims; http://www.fda.gov/downloads/Drugs/ Guidances/UCM193282.pdf, 2009. 7. Tack J, Carbone F. Overlap between postprandial distress syndrome and epigastric pain syndrome in the DIAMOND study. Am J Gastroenterol 2013;108:1808–10 (this issue). 1

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; 2 Astra Zeneca Research, Mölndal, Sweden. Correspondence: Nimish Vakil, MD, FACG, AGAF, FASGE, FACP, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53066, USA. E-mail: [email protected]

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