- Email: [email protected]
Functional gastrointestinal disease: has the genomic era arrived?
April 2004
EDITORIALS
30. Wylie AA, Murphy SK, Orton TC, Jirtle RL. Novel imprinted DLK1/ GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation. Genome Res 2000;10:1711–1718. 31. Sullivan MJ, Taniguchi T, Jhee A, Kerr N, Reeve AE. Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene 1999;18:7527–7534. 32. Killian JK, Nolan CM, Wylie AA, Li T, Vu TH, Hoffman AR, Jirtle RL. Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary. Hum Mol Genet 2001;10:1721–1728. 33. Paulsen M, El-Maarri O, Engemann S, Strodicke M, Franck O, Davies K, Reinhardt R, Reik W, Walter J. Sequence conservation and variability of imprinting in the Beckwith–Wiedemann syn-
1193
drome gene cluster in human and mouse. Hum Mol Genet 2000; 9:1829 –1841.
Address requests for reprints to: Randy L. Jirtle, Ph.D, Department of Radiation Oncology, Duke University Medical Center, Box 3433, Durham, North Carolina 27710. e-mail: [email protected]; fax: (919) 684-5584. Supported by National Institutes of Health Grants CA25951 and ES08823. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.02.026
Functional Gastrointestinal Disease: Has the Genomic Era Arrived? See article on page 971.
unctional gastrointestinal disorders (FGIDs) are common, disabling, poorly understood, and bereft of curative therapy. Within the broad canvas that is functional gastrointestinal disease are found all of those patients with a symptom or, more usually, symptoms apparently originating from the gut, yet in whom conventional endoscopic, radiologic, serologic, manometric, and pathologic studies fail to uncover any abnormality of diagnostic significance. For some time, clinicians have recognized a tendency for some of the more common of the many and varied functional symptoms to aggregate into 2 major “clusters” which, in turn, tend to focus on either the upper or lower gut. These 2 primary groupings of FGIDs are more commonly recognized as functional dyspepsia (FD) and irritable bowel syndrome (IBS), respectively. Though some have counselled against such an approach, insisting that unexplained symptoms should be recognized as such and no more,1 the syndromatic approach to FGIDs, supported, in part, by clinical studies and expert opinion, has held sway and has led to the recognition and acceptance of both FD and IBS as valid targets for investigative and therapeutic research.2 FGIDs have, in essence, become “respectable” and one can now admit openly to a clinical or research interest in FD or IBS without attracting condescending glances and even opprobrium from fellow academics, funding authorities and peer-reviewed journals, alike. Even more tantalizing for the newly accepted “functionologists” have been recent descriptions of disrupted physiology, subtle pathologic abnormalities and even genetic predisposition in FGIDs; are these disorders
F
functional after all? On the physiological front, both FD and IBS have been associated with abnormalities of motor function,3 visceral hypersensitivity,3 autonomic function,4 and cerebral perception. Reports of the precipitation of both of these functional disorders by infectious agents are now extant in the literature.5–7 Especially impressive is the association between IBS and prior bacterial gastroenteritis; the natural history, predisposing factors and functional and pathologic correlates of this particular relationship are now well documented.6,7 Equally provocative are very recent reports, of firstly, inflammatory cell activation, in the colon, among unselected IBS patients, regardless of the nature of onset or symptom predominance,8 and, secondly, of epithelial and myenteric plexus inflammation, in the jejunum, in a group of patients with severe IBS9; taken together, these studies suggest an immunological basis for IBS.10 Our current knowledge of mucosal immunology and its interactions with the gut flora, as well as experimental models of immune-motor and immune-sensory interactions have, in turn, provided a conceptual framework within which one can construct direct links between a luminal trigger, a mucosal immune response and symptom-generating alterations in enteric myoneural function.11–13 As in all other hypotheses of infectious initiation of chronic unexplained disease, a genetic predisposition is assumed to lay the groundwork and thus explain why not all exposed develop the disorder under study. Evidence for such a predisposition, indeed, exists for some FGIDs14 –16 and is now further supported by the study from Holtmann et al. reported in this issue of GASTROENTEROLOGY.17 Taken to its limits, the infection/ inflammation hypothesis would appear, therefore, and for the first time, to square the circle in IBS and FGIDs?
1194
EDITORIALS
Science, Medicine, and Life Are Never That Simple The problems with FGIDs, and FD, in particular, begin with their very definition. Any disorder whose definition is based soley on the presence or absence of a common and nonspecific symptom is prey to many confounding variables. In the study by Holtmann et al. FGIDs were defined using the Bowel Disease Questionnaire and according to the Rome II criteria. Despite the widespread acceptance of these instruments in FGIDs and IBS, in particular, the integrity and reproducibility, over time, of the definition of FD, derived according this strategy, are not beyond question.18 Indeed, the problems associated with the issue of definition are evident within this very study; many of the subjects demonstrated significant overlap between FD and IBS (74% of FD subjects in study A had symptoms consistent with IBS!); how should such overlap patients be categorized? To which FGID do we ascribe an association if one is found? It is interesting that these authors focused on FD and found, indeed, more evidence for an association between the 825 CC genotype and FD when there is, to date, a more convincing basis for a genetic predisposition in IBS,14 –16 a diagnosis which clinicians regard as more coherent and stable than FD.19 That the 825 CC association failed to hold for the IBS subpopulation in Holtmann’s study will strike many as counterintuitive but may have reflected a lack of power to perform such detailed subgroup analysis. However, it must also be stated that the association with the CC phenotype for this gene which encodes for the  3 subunit of Gproteins held up in the 2 different study groups reported by Holtmann et al.17 The risk attributable to the CC genotype in FD must be low, however, as its prevalence in FD exceeded that of controls by ⬍ 20%. How significant is this finding, therefore? Genetic polymorphisms are extremely common and may have no relevance to disease; the interpretation of studies of polymorphisms is therefore fraught with difficulties.20 –22 In 1 recent assessment of 55 meta-analyses of genetic associations, only 9 replicated the proposed association; small studies appeared most to blame for unsubstantiated claims.20 This issue must be especially problematic for a polymorphism as frequent in the general population as that reported by Holtmann et al., here genuine heterogeneity could be prominent. Though Holtmann et al. did take steps to minimize its impact, population stratification can also, inadvertently, contribute to spurious associations in this context.21 They acknowledge the possible contributions of such confounding factors as comorbid psychopathology, a major determinant of disease expression in FGIDs; others such
GASTROENTEROLOGY Vol. 126, No. 4
as age and prior drug therapy may have also contributed in some of their subjects. Statistical issues may also come in to play; some have questioned the appropriateness of a P value set at 0.05 in association studies.22 A cursory glimpse at the literature reveals, not surprisingly, given the biological function of the gene product, a host of proposed associations between polymorphisms in the G protein  subunit gene and such common diseases as hypertension, depression, and obesity. It is noteworthy, however, that findings are not universally consistent between studies in the same disorder. If this genotype is associated with FD, what is it doing? Holtmann et al. speculate on potential roles in enteric myoneural activity, central perception, hypothlalmic-pituitary axis (HPA) function and the inflammatory response.17 However, the relative contributions of these and other factors to the pathophysiology of FD remains unclear; while various groups have identified impaired accommodation, delayed gastric emptying, visceral hypersensitivity,3 as well as autonomic and HPA dysfunction4 as pathogenetic mechanisms in FD, the prevalence of any one of these findings and their relationships to particular symptoms have varied significantly between studies. Furthermore, the contribution of Helicobacter pylori, the most widely promoted infectious trigger for FD, is, at best, highly controversial. At present, therefore, gene-product-function correlations are quite impossible in FD and it is nigh impossible to place this intriguing finding in a clinical context. All would agree that FD is a heterogenous disorder; what remain to be defined are the contributors to this heterogeneity, be they environmental, pathological, or psychological. The study presented by Holtmann et al., suggests, at the very least, that genetic variation may be one such factor; whether the genotype described relates to one, as yet to be defined, subgroup of FD or to FD, in general, remains to be defined. Given the high prevalence of the CC genotype among control subjects and the relatively modest excess of the genotype in the FD subjects, the former would appear more plausible. Concerns regarding definition, heterogeneity and methodology notwithstanding, this and other studies point FGID research in a new direction, which we are obliged, in the interest of our patients, to follow. EAMONN M. M. QUIGLEY Department of Medicine National University of Ireland Cork; and Alimentary Pharmabiotic Centre Biosciences Institute University College Cork Cork, Ireland
April 2004
EDITORIALS
References 1. Christensen J. The pathophysiology of the irritable bowel syndrome. Lancet 1992;340:1444 –1447. 2. Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE. Rome II, The functional gastrointestinal disorders. (2nd ed). McLean, Virginia: Degnon Associates, 2000. 3. Fischler B, Tack J, De Gucht V, Shkedy ZI, Persoons P, Broekaert D, Molenberghs G, Janssens J. Heterogeneity of symptom pattern, psychosocial factors, and pathophysiological mechanisms in severe functional dyspepsia. Gastroenterology 2003;124: 903–910. 4. Dinan TG, Scott LV, Brady D, McNamara D, Keeling PWN. Altered hypothalamic cholinergic responses in patients with nonulcer dyspepsia: a study of pyridostigmine-stimulated growth hormone release. Am J Gastroenterol 2002;97:1937–1940. 5. Tack J, Demedts I, Dehondt G, Caenepeel P, Fischler B, Zandecki M, Janssens J. Clinical and pathophysiogical characterisitics of acute-onset functional dyspepsia. Gastroenterology 2002;122: 1738 –1747. 6. Spiller RC. Estimating the importance of infection in IBS. Am J Gastroenterol 2003;98:238 –241. 7. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003;125:1651–1659. 8. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778 –1783. 9. Tornblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002;123:1972– 1979. 10. Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology 2002;122:2078 –2080. 11. Collins SM. Stress and the gastrointestinal tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance. Am J Physiol 2001;280:G315–G318. 12. Mayer EA, Collins SM. Evolving pathophysiological models of functional gastrointestinal disorders. Gastroenterology 2002;122: 2032–2048.
1195
13. Spiller RC. Role of nerves in enteric infection. Gut 2002;51:759 – 762. 14. Locke GR III, Zinsmeister AR, Talley NJ, Fett SL, Melton L J III. Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc 2000;75:907–912. 15. Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G. Evidence for a genetic contribution to functional bowel disorder. Am J Gastroenterol 1998;93:1311–1317. 16. Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology 2001;121:799 – 804. 17. Holtmann G, Siffert W, Haag S, Mueller N, Langkafel M, Senf W, Zotz R, Talley NJ. G-protein 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 2004;126;971–979. 18. Locke GR III. Prevalence, incidence and natural history of dyspepsia and functional dyspepsia. Baillieres Clin Gastroenterol 1998;12:435– 442. 19. Locke GR III. Natural history of irritable bowel syndrome and durability of the diagnosis. Rev Gastroenterol Disord 2003; 3(Suppl. 3):S12–S17. 20. Ioannidis JPA, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG. Genetic associations in large versus small studies: an empirical assessment. Lancet 2003;361:567–571. 21. Cardon LR, Plamer LJ. Population stratification and spurious allelic association. Lancet 2003;361:598 – 604. 22. Colhoun HM, McKeigue PM, Davey-Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361:865– 872.
Address requests for reprints to: Eamonn M. M. Quigley, M.D., F.R.C.P., F.A.C.P., F.A.C.G., F.R.C.P.I., Department of Medicine, Clinical Sciences Building, Cork University Hospital, Cork, Ireland. e-mail: [email protected]; fax: (353) 21 490 1289. Supported by grants from Science Foundation Ireland. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.02.028
Prophylactic Antibiotic Use in Severe Acute Pancreatitis: Hemlock, Help, or Hype? See article on page 997.
cute pancreatitis (AP) is a significant health problem in the United States, with a yearly incidence of 49.5 per 100,000.1 Annual hospitalization costs associated with AP exceed $1.7 billion, and disease-associated morbidity results in at least $250 million in yearly losses because of decreased worker productivity.2 Despite extensive research into potential therapies for AP, the in-hospital case mortality rate for severe AP has remained at approximately 5%–10%.3 Almost all deaths caused by AP occur in individuals with severe AP (SAP). SAP is defined as AP associated
A
with 1 or more of the following features: (1) ⬎one-third necrosis of the pancreas; (2) organ failure (indicated by systolic blood pressure ⱕ90 mm Hg, serum creatinine ⬎2.0 mg/dL, ⬎500 mL of gastrointestinal blood loss in 24 hours, or PaO2ⱕ60)4; and (3) development of local complications such as hemorrhage, abscess, or pseudocyst. Early deaths due to SAP are generally caused by massive inflammatory responses that result in multisystem organ failure.5 This inflammatory response is very similar to the systemic inflammatory response syndrome, which is responsible for multisystem organ failure in cases of severe sepsis and trauma.6 Several investigators have attempted to identify therapeutic agents to dimin-
EDITORIALS
30. Wylie AA, Murphy SK, Orton TC, Jirtle RL. Novel imprinted DLK1/ GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation. Genome Res 2000;10:1711–1718. 31. Sullivan MJ, Taniguchi T, Jhee A, Kerr N, Reeve AE. Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene 1999;18:7527–7534. 32. Killian JK, Nolan CM, Wylie AA, Li T, Vu TH, Hoffman AR, Jirtle RL. Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary. Hum Mol Genet 2001;10:1721–1728. 33. Paulsen M, El-Maarri O, Engemann S, Strodicke M, Franck O, Davies K, Reinhardt R, Reik W, Walter J. Sequence conservation and variability of imprinting in the Beckwith–Wiedemann syn-
1193
drome gene cluster in human and mouse. Hum Mol Genet 2000; 9:1829 –1841.
Address requests for reprints to: Randy L. Jirtle, Ph.D, Department of Radiation Oncology, Duke University Medical Center, Box 3433, Durham, North Carolina 27710. e-mail: [email protected]; fax: (919) 684-5584. Supported by National Institutes of Health Grants CA25951 and ES08823. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.02.026
Functional Gastrointestinal Disease: Has the Genomic Era Arrived? See article on page 971.
unctional gastrointestinal disorders (FGIDs) are common, disabling, poorly understood, and bereft of curative therapy. Within the broad canvas that is functional gastrointestinal disease are found all of those patients with a symptom or, more usually, symptoms apparently originating from the gut, yet in whom conventional endoscopic, radiologic, serologic, manometric, and pathologic studies fail to uncover any abnormality of diagnostic significance. For some time, clinicians have recognized a tendency for some of the more common of the many and varied functional symptoms to aggregate into 2 major “clusters” which, in turn, tend to focus on either the upper or lower gut. These 2 primary groupings of FGIDs are more commonly recognized as functional dyspepsia (FD) and irritable bowel syndrome (IBS), respectively. Though some have counselled against such an approach, insisting that unexplained symptoms should be recognized as such and no more,1 the syndromatic approach to FGIDs, supported, in part, by clinical studies and expert opinion, has held sway and has led to the recognition and acceptance of both FD and IBS as valid targets for investigative and therapeutic research.2 FGIDs have, in essence, become “respectable” and one can now admit openly to a clinical or research interest in FD or IBS without attracting condescending glances and even opprobrium from fellow academics, funding authorities and peer-reviewed journals, alike. Even more tantalizing for the newly accepted “functionologists” have been recent descriptions of disrupted physiology, subtle pathologic abnormalities and even genetic predisposition in FGIDs; are these disorders
F
functional after all? On the physiological front, both FD and IBS have been associated with abnormalities of motor function,3 visceral hypersensitivity,3 autonomic function,4 and cerebral perception. Reports of the precipitation of both of these functional disorders by infectious agents are now extant in the literature.5–7 Especially impressive is the association between IBS and prior bacterial gastroenteritis; the natural history, predisposing factors and functional and pathologic correlates of this particular relationship are now well documented.6,7 Equally provocative are very recent reports, of firstly, inflammatory cell activation, in the colon, among unselected IBS patients, regardless of the nature of onset or symptom predominance,8 and, secondly, of epithelial and myenteric plexus inflammation, in the jejunum, in a group of patients with severe IBS9; taken together, these studies suggest an immunological basis for IBS.10 Our current knowledge of mucosal immunology and its interactions with the gut flora, as well as experimental models of immune-motor and immune-sensory interactions have, in turn, provided a conceptual framework within which one can construct direct links between a luminal trigger, a mucosal immune response and symptom-generating alterations in enteric myoneural function.11–13 As in all other hypotheses of infectious initiation of chronic unexplained disease, a genetic predisposition is assumed to lay the groundwork and thus explain why not all exposed develop the disorder under study. Evidence for such a predisposition, indeed, exists for some FGIDs14 –16 and is now further supported by the study from Holtmann et al. reported in this issue of GASTROENTEROLOGY.17 Taken to its limits, the infection/ inflammation hypothesis would appear, therefore, and for the first time, to square the circle in IBS and FGIDs?
1194
EDITORIALS
Science, Medicine, and Life Are Never That Simple The problems with FGIDs, and FD, in particular, begin with their very definition. Any disorder whose definition is based soley on the presence or absence of a common and nonspecific symptom is prey to many confounding variables. In the study by Holtmann et al. FGIDs were defined using the Bowel Disease Questionnaire and according to the Rome II criteria. Despite the widespread acceptance of these instruments in FGIDs and IBS, in particular, the integrity and reproducibility, over time, of the definition of FD, derived according this strategy, are not beyond question.18 Indeed, the problems associated with the issue of definition are evident within this very study; many of the subjects demonstrated significant overlap between FD and IBS (74% of FD subjects in study A had symptoms consistent with IBS!); how should such overlap patients be categorized? To which FGID do we ascribe an association if one is found? It is interesting that these authors focused on FD and found, indeed, more evidence for an association between the 825 CC genotype and FD when there is, to date, a more convincing basis for a genetic predisposition in IBS,14 –16 a diagnosis which clinicians regard as more coherent and stable than FD.19 That the 825 CC association failed to hold for the IBS subpopulation in Holtmann’s study will strike many as counterintuitive but may have reflected a lack of power to perform such detailed subgroup analysis. However, it must also be stated that the association with the CC phenotype for this gene which encodes for the  3 subunit of Gproteins held up in the 2 different study groups reported by Holtmann et al.17 The risk attributable to the CC genotype in FD must be low, however, as its prevalence in FD exceeded that of controls by ⬍ 20%. How significant is this finding, therefore? Genetic polymorphisms are extremely common and may have no relevance to disease; the interpretation of studies of polymorphisms is therefore fraught with difficulties.20 –22 In 1 recent assessment of 55 meta-analyses of genetic associations, only 9 replicated the proposed association; small studies appeared most to blame for unsubstantiated claims.20 This issue must be especially problematic for a polymorphism as frequent in the general population as that reported by Holtmann et al., here genuine heterogeneity could be prominent. Though Holtmann et al. did take steps to minimize its impact, population stratification can also, inadvertently, contribute to spurious associations in this context.21 They acknowledge the possible contributions of such confounding factors as comorbid psychopathology, a major determinant of disease expression in FGIDs; others such
GASTROENTEROLOGY Vol. 126, No. 4
as age and prior drug therapy may have also contributed in some of their subjects. Statistical issues may also come in to play; some have questioned the appropriateness of a P value set at 0.05 in association studies.22 A cursory glimpse at the literature reveals, not surprisingly, given the biological function of the gene product, a host of proposed associations between polymorphisms in the G protein  subunit gene and such common diseases as hypertension, depression, and obesity. It is noteworthy, however, that findings are not universally consistent between studies in the same disorder. If this genotype is associated with FD, what is it doing? Holtmann et al. speculate on potential roles in enteric myoneural activity, central perception, hypothlalmic-pituitary axis (HPA) function and the inflammatory response.17 However, the relative contributions of these and other factors to the pathophysiology of FD remains unclear; while various groups have identified impaired accommodation, delayed gastric emptying, visceral hypersensitivity,3 as well as autonomic and HPA dysfunction4 as pathogenetic mechanisms in FD, the prevalence of any one of these findings and their relationships to particular symptoms have varied significantly between studies. Furthermore, the contribution of Helicobacter pylori, the most widely promoted infectious trigger for FD, is, at best, highly controversial. At present, therefore, gene-product-function correlations are quite impossible in FD and it is nigh impossible to place this intriguing finding in a clinical context. All would agree that FD is a heterogenous disorder; what remain to be defined are the contributors to this heterogeneity, be they environmental, pathological, or psychological. The study presented by Holtmann et al., suggests, at the very least, that genetic variation may be one such factor; whether the genotype described relates to one, as yet to be defined, subgroup of FD or to FD, in general, remains to be defined. Given the high prevalence of the CC genotype among control subjects and the relatively modest excess of the genotype in the FD subjects, the former would appear more plausible. Concerns regarding definition, heterogeneity and methodology notwithstanding, this and other studies point FGID research in a new direction, which we are obliged, in the interest of our patients, to follow. EAMONN M. M. QUIGLEY Department of Medicine National University of Ireland Cork; and Alimentary Pharmabiotic Centre Biosciences Institute University College Cork Cork, Ireland
April 2004
EDITORIALS
References 1. Christensen J. The pathophysiology of the irritable bowel syndrome. Lancet 1992;340:1444 –1447. 2. Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE. Rome II, The functional gastrointestinal disorders. (2nd ed). McLean, Virginia: Degnon Associates, 2000. 3. Fischler B, Tack J, De Gucht V, Shkedy ZI, Persoons P, Broekaert D, Molenberghs G, Janssens J. Heterogeneity of symptom pattern, psychosocial factors, and pathophysiological mechanisms in severe functional dyspepsia. Gastroenterology 2003;124: 903–910. 4. Dinan TG, Scott LV, Brady D, McNamara D, Keeling PWN. Altered hypothalamic cholinergic responses in patients with nonulcer dyspepsia: a study of pyridostigmine-stimulated growth hormone release. Am J Gastroenterol 2002;97:1937–1940. 5. Tack J, Demedts I, Dehondt G, Caenepeel P, Fischler B, Zandecki M, Janssens J. Clinical and pathophysiogical characterisitics of acute-onset functional dyspepsia. Gastroenterology 2002;122: 1738 –1747. 6. Spiller RC. Estimating the importance of infection in IBS. Am J Gastroenterol 2003;98:238 –241. 7. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003;125:1651–1659. 8. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778 –1783. 9. Tornblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002;123:1972– 1979. 10. Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology 2002;122:2078 –2080. 11. Collins SM. Stress and the gastrointestinal tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance. Am J Physiol 2001;280:G315–G318. 12. Mayer EA, Collins SM. Evolving pathophysiological models of functional gastrointestinal disorders. Gastroenterology 2002;122: 2032–2048.
1195
13. Spiller RC. Role of nerves in enteric infection. Gut 2002;51:759 – 762. 14. Locke GR III, Zinsmeister AR, Talley NJ, Fett SL, Melton L J III. Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc 2000;75:907–912. 15. Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G. Evidence for a genetic contribution to functional bowel disorder. Am J Gastroenterol 1998;93:1311–1317. 16. Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology 2001;121:799 – 804. 17. Holtmann G, Siffert W, Haag S, Mueller N, Langkafel M, Senf W, Zotz R, Talley NJ. G-protein 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 2004;126;971–979. 18. Locke GR III. Prevalence, incidence and natural history of dyspepsia and functional dyspepsia. Baillieres Clin Gastroenterol 1998;12:435– 442. 19. Locke GR III. Natural history of irritable bowel syndrome and durability of the diagnosis. Rev Gastroenterol Disord 2003; 3(Suppl. 3):S12–S17. 20. Ioannidis JPA, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG. Genetic associations in large versus small studies: an empirical assessment. Lancet 2003;361:567–571. 21. Cardon LR, Plamer LJ. Population stratification and spurious allelic association. Lancet 2003;361:598 – 604. 22. Colhoun HM, McKeigue PM, Davey-Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361:865– 872.
Address requests for reprints to: Eamonn M. M. Quigley, M.D., F.R.C.P., F.A.C.P., F.A.C.G., F.R.C.P.I., Department of Medicine, Clinical Sciences Building, Cork University Hospital, Cork, Ireland. e-mail: [email protected]; fax: (353) 21 490 1289. Supported by grants from Science Foundation Ireland. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.02.028
Prophylactic Antibiotic Use in Severe Acute Pancreatitis: Hemlock, Help, or Hype? See article on page 997.
cute pancreatitis (AP) is a significant health problem in the United States, with a yearly incidence of 49.5 per 100,000.1 Annual hospitalization costs associated with AP exceed $1.7 billion, and disease-associated morbidity results in at least $250 million in yearly losses because of decreased worker productivity.2 Despite extensive research into potential therapies for AP, the in-hospital case mortality rate for severe AP has remained at approximately 5%–10%.3 Almost all deaths caused by AP occur in individuals with severe AP (SAP). SAP is defined as AP associated
A
with 1 or more of the following features: (1) ⬎one-third necrosis of the pancreas; (2) organ failure (indicated by systolic blood pressure ⱕ90 mm Hg, serum creatinine ⬎2.0 mg/dL, ⬎500 mL of gastrointestinal blood loss in 24 hours, or PaO2ⱕ60)4; and (3) development of local complications such as hemorrhage, abscess, or pseudocyst. Early deaths due to SAP are generally caused by massive inflammatory responses that result in multisystem organ failure.5 This inflammatory response is very similar to the systemic inflammatory response syndrome, which is responsible for multisystem organ failure in cases of severe sepsis and trauma.6 Several investigators have attempted to identify therapeutic agents to dimin-