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Functional Bowel Symptoms in Quiescent Inflammatory Bowel Disease: More Than Just Irritable Bowel Syndrome?
1176 Selected Summaries
FUNCTIONAL BOWEL SYMPTOMS IN QUIESCENT INFLAMMATORY BOWEL DISEASE: MORE THAN JUST IRRITABLE BOWEL SYNDROME? Vivinus-Nébot M, Frin-Mathy G, Bzioueche H, et al. Functional bowel symptoms in quiescent IBD: role of epithelial barrier disruption and low grade inflammation. Gut 2014;63:744–752. Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD) result from a complex interaction between host genetic factors and the mucosal immune system, as well as disruption of the intestinal epithelial barrier and the intestinal microbiota. At present, the mainstay of treatment targets modulation of the intestinal immune system, but this approach fails to address a subset of individuals who have persistent symptoms, in the absence of quantifiable disease activity. Given that irritable bowel syndrome (IBS) is so common in the community (Clin Gastroenterol Hepatol 2012;10:712–721), such individuals may be presumed to have coincidental functional abdominal symptoms akin to those of IBS (Nat Rev Gastroenterol Hepatol 2013;10:58–61). However, it remains unclear whether IBS-type symptoms in quiescent IBD reflect true coincident IBS or ongoing low-grade mucosal inflammation. The authors carried out a prospective case-control study whose primary aim was to identify whether subclinical inflammation contributes to the development of IBS-like symptoms in individuals with clinically quiescent IBD. They recruited IBD patients in remission (n ¼ 49; n ¼ 18 UC, n ¼ 31 CD), IBS patients (n ¼ 51), and healthy controls (n ¼ 27) undergoing ileocolonoscopy. Each participant had 12 biopsy specimens taken from the cecum and completed questionnaires evaluating the severity of IBS symptoms. Quiescent IBD individuals were defined as those meeting specified criteria including a physicians’ global assessment confirming disease remission, C-reactive protein <10 mg/L, erythrocyte sedimentation rate <20 mm/h, platelet count <450 1012/L, white cell count <11 109/L, no glucocorticosteroid use for 12 months, a CD activity index of 150 or an UC activity index of 3, and macroscopically normal-appearing mucosa on ileocolonoscopy. The Rome III criteria were used to diagnose IBS or IBStype symptoms in those fulfilling criteria for quiescent CD or UC. Subjects with Rome III IBS were subcategorized into IBS with diarrhea, IBS with constipation, or IBS with mixed stool pattern. Patients with IBD were subgrouped into those with and without IBS-type symptoms (UC IBSþ, UC IBS-, CD IBSþ, CD IBS-). None of the IBS patients had a postinfectious etiology, and none were taking glucocorticosteroids or nonsteroidal anti-inflammatory drugs. Individuals with coexisting disease, including psychiatric illness, were excluded. IBS symptoms were assessed using the validated IBS severity scoring system (Aliment Pharmacol Ther 1997;
Gastroenterology Vol. 147, No. 5
11:395–402). Biopsy specimens were assessed for proinflammatory cell infiltrates, including mast cells, intraepithelial lymphocytes, and eosinophils, as well as immunohistochemistry for CD-117 and CD-3. Colonic paracellular permeability was measured by calculation of mean fluorescein concentrations in nanograms per milliliter at 180 minutes post addition of fluorescein-5.6 sulfonic acid to four biopsies. Tumor necrosis factor (TNF)-a levels were measured by enzyme-linked immunosorbent assay of conditioned medium from 2 colonic biopsies. Messenger RNA (mRNA) expression of the tight junction proteins ZO-1, a-catenin, and occludin was performed using quantitative real-time polymerase chain reaction. Of the patients with IBD in remission, 35.4% of CD and 38% of UC patients fulfilled the Rome III criteria for IBS. Disease extent, duration of disease, treatment, age, and sex did not influence likelihood of reporting IBS-type symptoms in IBD subjects. There was a significant difference in IBS severity scores between all subtypes of IBS and IBD individuals versus controls. Paracellular permeability was significantly higher in IBS patients compared with controls, with no differences observed between IBS subtypes. IBD patients with IBS-type symptoms had significantly greater paracellular permeability than those without (CD IBSþ vs CD IBS- [P ¼ .04]; UC IBSþ vs UC IBS- [P ¼ .03]). UC and CD individuals with IBS-type symptoms (IBD IBSþ) had similar paracellular permeability to those with IBS, whereas UC and CD participants without IBS-type symptoms (IBD IBS-) displayed comparable permeability to that of controls. Paracellular permeability correlated with IBS severity scores for the IBS, CD and UC populations. mRNA expression of ZO-1, a-catenin, and occludin was significantly reduced in IBS and IBD individuals versus controls, with a further reduction in ZO-1 and a-catenin observed between UC IBSþ and CD IBSþ versus UC IBS- and CD IBS-, respectively. Cecal biopsy mast cell concentration was significantly higher in all IBS and IBD subgroups versus controls. However, no difference was observed between IBD IBSþ and IBD IBS- patients. Intraepithelial lymphocytes were observed in higher numbers in all IBD groups versus IBS groups, regardless of the presence of IBS-type symptoms. There was a significantly higher intraepithelial lymphocyte count observed for both UC IBSþ and CD IBSþ versus UC IBS- and CD IBS- individuals, respectively. The only demonstrable difference in eosinophil count was observed between UC individuals versus controls, with no trend identified between UC IBSþ and UC IBS- subgroups, or any CD or IBS subgroup versus controls. Finally, there was a significant increase in TNF-a mRNA expression in both UC IBSþ and CD IBSþ individuals compared with the UC IBSand CD IBS- groups (P < .001 for both), but this did not translate into a significant difference in TNF-a protein expression between the same groups (P ¼ .06 for both). TNF-a protein expression was, however, significantly higher in all IBD subgroups, apart from UC IBS-, compared with IBS patients and controls (P < .01). Comment. IBS and IBD are classically described as dichotomous conditions, falling on either side of a
November 2014
functional–organic divide. The etiology of each condition is incompletely understood, but it is now recognized that some mechanisms implicated in the pathogenesis of each condition may be common to both, including immune dysregulation, intestinal barrier dysfunction, and an altered microbiome (Curr Opin Gastroenterol 2014;30:352–358). In everyday practice, the distinction between IBS-type symptoms in quiescent IBD and symptoms arising from occult IBD activity can be difficult on clinical grounds alone, and may lead to uncertainty in management, with the potential for unnecessary invasive investigations and use of potent immunosuppressant medication, with potential side effects and a significant financial burden. Given these uncertainties, further investigation of the cause of ongoing gastrointestinal symptoms in individuals with clinically quiescent IBD, including the relationship between IBD/IBS-related dysbiosis and intestinal barrier dysfunction, is desirable, and the current study is therefore welcomed. Symptoms compatible with IBS are common in quiescent IBD (Am J Gastroenterol 2010;105:1788–1794; Aliment Pharmacol Ther 2013;38:44–51). Their prevalence in cases of IBD in this series is in keeping with a recent systematic review and meta-analysis examining functional bowel-type symptoms in IBD, which estimated a combined prevalence of 35%–40% in CD and UC patients in clinical remission (Am J Gastroenterol 2012;107:1474–1482). The findings presented by Vivinus-Nebot et al suggest some shared mechanisms for the development of IBS-type symptoms in both patients with IBS and those with IBD. The similarity in reduction of tight junction protein expression and increase in paracellular permeability supports the theory that a reduction in intestinal integrity leads to the development of pain symptoms, an observation that has been described previously (Neurogastroenterol Motil 2014;26:316–325). However, the mechanism by which this increased paracellular permeability occurs remains uncertain, with the authors’ findings supporting occult inflammation as the most likely cause in IBD IBSþ individuals, as evidenced by an increased inflammatory cell infiltrate and increased proinflammatory cytokine mRNA expression, although this did not seem to translate into increased TNF-a protein expression. Given that this is a commonly encountered problem in clinical practice, it is important to consider how best to assess and manage such patients. Clinical indices of IBD activity, including the CD activity index, do not seem to discriminate between Crohn’s activity and IBS (Aliment Pharmacol Ther 2013;37:786–794). Alternative methods of assessment are therefore required. Fecal biomarkers of mucosal inflammation, such as calprotectin, are one possibility and have been shown to be accurate in distinguishing IBD from IBS (Gut 2000;47:506–513). Calprotectin levels have been shown to be elevated in IBD patients in clinical remission with IBS-type symptoms in one study, suggesting that subclinical disease activity is the cause (Am J Gastroenterol 2010;105:1788–1794). This differentiation between IBS-type symptoms and those secondary to ongoing occult active inflammation is important, given that the efficacy of both immunomodulator and biologic therapy seems to be
Selected Summaries 1177
lower in IBD patients with abnormal clinical activity indices but with normal serum inflammatory markers (N Engl J Med 2010;362:1383–1395). In conclusion, this study implicates increased paracellular permeability as a potential cause for the development of symptoms compatible with IBS in patients with quiescent IBD, and highlights the fact that its development may be secondary to ongoing occult inflammation, rather than true functional bowel disease coexisting in a proportion of patients with IBD in remission. Studies comparing the fecal microbiome in patients with quiescent IBD who report IBS-type symptoms, which are linked to disease assessment using fecal biomarkers of inflammation, may further elucidate underlying mechanisms that could be driving the inflammatory process in this patient group. DAVID J. GRACIE ALEXANDER C. FORD Leeds Gastroenterology Institute St. James’s University Hospital and Leeds Institute of Biomedical and Clinical Sciences University of Leeds Leeds, United Kingdom
PROPHYLAXIS OF REBLEEDING IN HEPATOCELLULAR CARCINOMA: PUSHING THE ENVELOPE OR A REAL CLINICAL BENEFIT? Ripoll C, Genescà J, Aruyo IK, et al. Rebleeding prophylaxis improves outcome in patients with hepatocellular carcinoma: a multicenter case-control study. Hepatology 2013; 58:2079–2088. In the last decades, hepatocellular carcinoma (HCC) has overtaken portal hypertension (PHT) as a dominant cause of death in patients with compensated cirrhosis of any etiology, yet evidence has accumulated that survival of HCC patients may significantly be jeopardized by events related to PHT (Semin Liver Dis 1999;19:329–338). However, treatment and prevention of PHT related events are far from being a standard of care in the management of HCC patients. This happens despite both pharmacologic and endoscopic treatment of PHT is known to provide survival benefits to HCC-free cirrhotic patients suffering from acute variceal bleeding (AVB), who ultimately remain exposed to a residual mortality rate of 10%–20% per episode compared with the 40%–60% in untreated patients (N Engl J Med 2010;362:823–832). Furthermore, the prognosis of patients recovering from AVB is improved by prevention of rebleeding. Although the risk of rebleeding may significantly be abated in risk patients through a combination of nonselective b-blockers and endoscopic band ligation, there are few data on the effectiveness of rebleeding prophylaxis in cirrhotic patients with a HCC who experienced an AVB episode. HCC, in fact, was an exclusion
FUNCTIONAL BOWEL SYMPTOMS IN QUIESCENT INFLAMMATORY BOWEL DISEASE: MORE THAN JUST IRRITABLE BOWEL SYNDROME? Vivinus-Nébot M, Frin-Mathy G, Bzioueche H, et al. Functional bowel symptoms in quiescent IBD: role of epithelial barrier disruption and low grade inflammation. Gut 2014;63:744–752. Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD) result from a complex interaction between host genetic factors and the mucosal immune system, as well as disruption of the intestinal epithelial barrier and the intestinal microbiota. At present, the mainstay of treatment targets modulation of the intestinal immune system, but this approach fails to address a subset of individuals who have persistent symptoms, in the absence of quantifiable disease activity. Given that irritable bowel syndrome (IBS) is so common in the community (Clin Gastroenterol Hepatol 2012;10:712–721), such individuals may be presumed to have coincidental functional abdominal symptoms akin to those of IBS (Nat Rev Gastroenterol Hepatol 2013;10:58–61). However, it remains unclear whether IBS-type symptoms in quiescent IBD reflect true coincident IBS or ongoing low-grade mucosal inflammation. The authors carried out a prospective case-control study whose primary aim was to identify whether subclinical inflammation contributes to the development of IBS-like symptoms in individuals with clinically quiescent IBD. They recruited IBD patients in remission (n ¼ 49; n ¼ 18 UC, n ¼ 31 CD), IBS patients (n ¼ 51), and healthy controls (n ¼ 27) undergoing ileocolonoscopy. Each participant had 12 biopsy specimens taken from the cecum and completed questionnaires evaluating the severity of IBS symptoms. Quiescent IBD individuals were defined as those meeting specified criteria including a physicians’ global assessment confirming disease remission, C-reactive protein <10 mg/L, erythrocyte sedimentation rate <20 mm/h, platelet count <450 1012/L, white cell count <11 109/L, no glucocorticosteroid use for 12 months, a CD activity index of 150 or an UC activity index of 3, and macroscopically normal-appearing mucosa on ileocolonoscopy. The Rome III criteria were used to diagnose IBS or IBStype symptoms in those fulfilling criteria for quiescent CD or UC. Subjects with Rome III IBS were subcategorized into IBS with diarrhea, IBS with constipation, or IBS with mixed stool pattern. Patients with IBD were subgrouped into those with and without IBS-type symptoms (UC IBSþ, UC IBS-, CD IBSþ, CD IBS-). None of the IBS patients had a postinfectious etiology, and none were taking glucocorticosteroids or nonsteroidal anti-inflammatory drugs. Individuals with coexisting disease, including psychiatric illness, were excluded. IBS symptoms were assessed using the validated IBS severity scoring system (Aliment Pharmacol Ther 1997;
Gastroenterology Vol. 147, No. 5
11:395–402). Biopsy specimens were assessed for proinflammatory cell infiltrates, including mast cells, intraepithelial lymphocytes, and eosinophils, as well as immunohistochemistry for CD-117 and CD-3. Colonic paracellular permeability was measured by calculation of mean fluorescein concentrations in nanograms per milliliter at 180 minutes post addition of fluorescein-5.6 sulfonic acid to four biopsies. Tumor necrosis factor (TNF)-a levels were measured by enzyme-linked immunosorbent assay of conditioned medium from 2 colonic biopsies. Messenger RNA (mRNA) expression of the tight junction proteins ZO-1, a-catenin, and occludin was performed using quantitative real-time polymerase chain reaction. Of the patients with IBD in remission, 35.4% of CD and 38% of UC patients fulfilled the Rome III criteria for IBS. Disease extent, duration of disease, treatment, age, and sex did not influence likelihood of reporting IBS-type symptoms in IBD subjects. There was a significant difference in IBS severity scores between all subtypes of IBS and IBD individuals versus controls. Paracellular permeability was significantly higher in IBS patients compared with controls, with no differences observed between IBS subtypes. IBD patients with IBS-type symptoms had significantly greater paracellular permeability than those without (CD IBSþ vs CD IBS- [P ¼ .04]; UC IBSþ vs UC IBS- [P ¼ .03]). UC and CD individuals with IBS-type symptoms (IBD IBSþ) had similar paracellular permeability to those with IBS, whereas UC and CD participants without IBS-type symptoms (IBD IBS-) displayed comparable permeability to that of controls. Paracellular permeability correlated with IBS severity scores for the IBS, CD and UC populations. mRNA expression of ZO-1, a-catenin, and occludin was significantly reduced in IBS and IBD individuals versus controls, with a further reduction in ZO-1 and a-catenin observed between UC IBSþ and CD IBSþ versus UC IBS- and CD IBS-, respectively. Cecal biopsy mast cell concentration was significantly higher in all IBS and IBD subgroups versus controls. However, no difference was observed between IBD IBSþ and IBD IBS- patients. Intraepithelial lymphocytes were observed in higher numbers in all IBD groups versus IBS groups, regardless of the presence of IBS-type symptoms. There was a significantly higher intraepithelial lymphocyte count observed for both UC IBSþ and CD IBSþ versus UC IBS- and CD IBS- individuals, respectively. The only demonstrable difference in eosinophil count was observed between UC individuals versus controls, with no trend identified between UC IBSþ and UC IBS- subgroups, or any CD or IBS subgroup versus controls. Finally, there was a significant increase in TNF-a mRNA expression in both UC IBSþ and CD IBSþ individuals compared with the UC IBSand CD IBS- groups (P < .001 for both), but this did not translate into a significant difference in TNF-a protein expression between the same groups (P ¼ .06 for both). TNF-a protein expression was, however, significantly higher in all IBD subgroups, apart from UC IBS-, compared with IBS patients and controls (P < .01). Comment. IBS and IBD are classically described as dichotomous conditions, falling on either side of a
November 2014
functional–organic divide. The etiology of each condition is incompletely understood, but it is now recognized that some mechanisms implicated in the pathogenesis of each condition may be common to both, including immune dysregulation, intestinal barrier dysfunction, and an altered microbiome (Curr Opin Gastroenterol 2014;30:352–358). In everyday practice, the distinction between IBS-type symptoms in quiescent IBD and symptoms arising from occult IBD activity can be difficult on clinical grounds alone, and may lead to uncertainty in management, with the potential for unnecessary invasive investigations and use of potent immunosuppressant medication, with potential side effects and a significant financial burden. Given these uncertainties, further investigation of the cause of ongoing gastrointestinal symptoms in individuals with clinically quiescent IBD, including the relationship between IBD/IBS-related dysbiosis and intestinal barrier dysfunction, is desirable, and the current study is therefore welcomed. Symptoms compatible with IBS are common in quiescent IBD (Am J Gastroenterol 2010;105:1788–1794; Aliment Pharmacol Ther 2013;38:44–51). Their prevalence in cases of IBD in this series is in keeping with a recent systematic review and meta-analysis examining functional bowel-type symptoms in IBD, which estimated a combined prevalence of 35%–40% in CD and UC patients in clinical remission (Am J Gastroenterol 2012;107:1474–1482). The findings presented by Vivinus-Nebot et al suggest some shared mechanisms for the development of IBS-type symptoms in both patients with IBS and those with IBD. The similarity in reduction of tight junction protein expression and increase in paracellular permeability supports the theory that a reduction in intestinal integrity leads to the development of pain symptoms, an observation that has been described previously (Neurogastroenterol Motil 2014;26:316–325). However, the mechanism by which this increased paracellular permeability occurs remains uncertain, with the authors’ findings supporting occult inflammation as the most likely cause in IBD IBSþ individuals, as evidenced by an increased inflammatory cell infiltrate and increased proinflammatory cytokine mRNA expression, although this did not seem to translate into increased TNF-a protein expression. Given that this is a commonly encountered problem in clinical practice, it is important to consider how best to assess and manage such patients. Clinical indices of IBD activity, including the CD activity index, do not seem to discriminate between Crohn’s activity and IBS (Aliment Pharmacol Ther 2013;37:786–794). Alternative methods of assessment are therefore required. Fecal biomarkers of mucosal inflammation, such as calprotectin, are one possibility and have been shown to be accurate in distinguishing IBD from IBS (Gut 2000;47:506–513). Calprotectin levels have been shown to be elevated in IBD patients in clinical remission with IBS-type symptoms in one study, suggesting that subclinical disease activity is the cause (Am J Gastroenterol 2010;105:1788–1794). This differentiation between IBS-type symptoms and those secondary to ongoing occult active inflammation is important, given that the efficacy of both immunomodulator and biologic therapy seems to be
Selected Summaries 1177
lower in IBD patients with abnormal clinical activity indices but with normal serum inflammatory markers (N Engl J Med 2010;362:1383–1395). In conclusion, this study implicates increased paracellular permeability as a potential cause for the development of symptoms compatible with IBS in patients with quiescent IBD, and highlights the fact that its development may be secondary to ongoing occult inflammation, rather than true functional bowel disease coexisting in a proportion of patients with IBD in remission. Studies comparing the fecal microbiome in patients with quiescent IBD who report IBS-type symptoms, which are linked to disease assessment using fecal biomarkers of inflammation, may further elucidate underlying mechanisms that could be driving the inflammatory process in this patient group. DAVID J. GRACIE ALEXANDER C. FORD Leeds Gastroenterology Institute St. James’s University Hospital and Leeds Institute of Biomedical and Clinical Sciences University of Leeds Leeds, United Kingdom
PROPHYLAXIS OF REBLEEDING IN HEPATOCELLULAR CARCINOMA: PUSHING THE ENVELOPE OR A REAL CLINICAL BENEFIT? Ripoll C, Genescà J, Aruyo IK, et al. Rebleeding prophylaxis improves outcome in patients with hepatocellular carcinoma: a multicenter case-control study. Hepatology 2013; 58:2079–2088. In the last decades, hepatocellular carcinoma (HCC) has overtaken portal hypertension (PHT) as a dominant cause of death in patients with compensated cirrhosis of any etiology, yet evidence has accumulated that survival of HCC patients may significantly be jeopardized by events related to PHT (Semin Liver Dis 1999;19:329–338). However, treatment and prevention of PHT related events are far from being a standard of care in the management of HCC patients. This happens despite both pharmacologic and endoscopic treatment of PHT is known to provide survival benefits to HCC-free cirrhotic patients suffering from acute variceal bleeding (AVB), who ultimately remain exposed to a residual mortality rate of 10%–20% per episode compared with the 40%–60% in untreated patients (N Engl J Med 2010;362:823–832). Furthermore, the prognosis of patients recovering from AVB is improved by prevention of rebleeding. Although the risk of rebleeding may significantly be abated in risk patients through a combination of nonselective b-blockers and endoscopic band ligation, there are few data on the effectiveness of rebleeding prophylaxis in cirrhotic patients with a HCC who experienced an AVB episode. HCC, in fact, was an exclusion