Mercè Rosinach

Drug consumption and the risk of microscopic colitis.

BACKGROUND:Microscopic colitis is a rare disease of unknown etiology. It has been described that some drugs could cause or worsen the disease; however, the scientific evidence is limited.AIM:To investigate the possible association of chronic drug consumption with microscopic colitis.METHODS:This was a case–control study in which groups of cases were Group 1–39 patients with collagenous colitis; Group 2–39 patients with lymphocytic colitis; and Group 3–52 patients with chronic watery diarrhea of functional characteristics. 103 subjects formed the control group. At diagnosis, a drug consumption history of at least 2-wk duration was registered. An age- and sex-adjusted logistic regression analysis was used, and the odds ratio (OR, 95% CI) was calculated.RESULTS:Drug consumption was more frequent in lymphocytic colitis than in the control group (92.3% vs 76.3%, P < 0.05). The mean daily number of drugs by person was also higher in lymphocytic colitis (3.79 ± 0.44 vs 2.13 ± 0.22, P = 0.04). The following associations as compared with the control group were observed: Group 1—Consumption of NSAIDs (46.2% vs 23%, OR 2.9, 1.3–6.4), selective serotonin reuptake inhibitors (SSRIs) (18% vs 1%, OR 21, 2.5–177), specifically, sertraline (15.4% vs 0%, P < 0.0005); Group 2—SSRIs (28% vs 1%, OR 37.7, 4.7–304), beta-blockers (13 vs 3%, OR 4.79, 1.04–20), statins (13% vs 3%, OR 4.6, 1.04–20), biphosphonates (8% vs 0%, P = 0.022); Group 3—SSRIs (15% vs 1%, OR 16.2, 2–135), statins (11.5% vs 3%, OR 5.4, 1.2–24). As compared with the chronic diarrhea group, a significant association with the usage of sertraline in LC (P = 0.005) and a trend for NSAIDs in CC (P = 0.057) were found.CONCLUSIONSDrug consumption increases the risk of microscopic colitis. Some drugs might be trigger factors of colonic inflammation in predisposed hosts, and others might only worsen self-evolving microscopic colitis.

Cytomegalovirus infection in ulcerative colitis: A prospective, comparative study on prevalence and diagnostic strategy

Background: Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), especially in severe, steroid‐refractory disease. However, its role in steroid‐refractoriness remains unknown. Our goals were to evaluate the prevalence of CMV disease in UC, the best diagnostic strategy, and the influence of disease activity and/or treatment in its development. Methods: Prospective, observational study including 114 subjects with active UC requiring intravenous steroids, steroid‐refractory UC, inactive UC on mesalamine, inactive UC on azathioprine, and healthy controls. CMV antibodies, pp65‐antigenemia, and rectal biopsies for hematoxylin and eosin staining, immunohistochemistry, and CMV‐pp67 mRNA were performed. These procedures were repeated after medical treatment only in patients with active UC. CMV disease was defined by the presence of inclusion bodies and/or positive immunohistochemistry in colonic biopsies. Results: CMV disease was found in 6 steroid‐refractory, CMV‐IgG‐positive UC patients but not among controls, inactive UC, or steroid‐responding UC patients. In 5 out of the 6 patients, CMV disease was diagnosed after 7–10 days on cyclosporine. Conclusions: CMV disease in UC only affects seropositive, steroid‐refractory UC patients. Steroid/cyclosporine treatment together with disease activity may predispose to latent colonic CMV reactivation. The impact of antiviral therapy on the clinical outcome of these patients remains to be elucidated.

Systematic Evaluation of the Causes of Chronic Watery Diarrhea With Functional Characteristics

BACKGROUND AND  AIMS:Causes of chronic watery diarrhea are multiple. There is not definite scientific evidence about which are the recommended explorations to be performed in the diagnostic workup of patients with functional diarrhea. The aim was to assess prospectively the presence of gluten-sensitive enteropathy, bile acid malabsorption, and sugar malabsorption in consecutive patients with chronic watery diarrhea of obscure origin fulfilling Rome II criteria of functional disease.METHODS:A total of 62 patients with chronic watery diarrhea, defined as more than 3 loose or liquid bowel movements a day for at least 4 wk and a stool weight >200 g/day were included. The following tests were performed: (a) HLA-DQ2/DQ8 genotyping, and if positive, endoscopic biopsies from distal duodenum were obtained, and intestinal damage assessed; (b) SeHCAT (Se-homotaurocholate) abdominal retention test; (c) small bowel follow-through; and (d) hydrogen breath test (lactose, fructose + sorbitol). Gluten- or sugar-free diet, or cholestyramine was administered according to results. Functional disease was diagnosed if all tests performed were normal or if either there was no response to specific therapy or diarrhea relapsed during a 12-month follow-up.RESULTS:Bile acid malabsorption was considered to be the cause of diarrhea in 28 (45.2%) patients, sugar malabsorption in 10 (16.1%), gluten-sensitive enteropathy in 10 (16.1%), and both bile acid and sugar malabsorption in 2 patients. Twelve (19.4%) patients remained without a specific diagnosis and were considered as functional bowel disease. Diarrhea stopped in the 50 patients after specific treatment, decreasing the daily stool number from 5.4 ± 0.3 to 1.5 ± 0.1 (P < 0.0005), without relapse after the 12-months follow-up.CONCLUSIONS:The diagnosis of functional disease in patients with chronic watery diarrhea should be performed with caution since in most cases there is an organic cause that justifies diarrhea.

Helicobacter pylori infection as a cause of iron deficiency anaemia of unknown origin

AIM To assess the aetiological role of Helicobacter pylori (H. pylori) infection in adult patients with iron-refractory or iron-dependent anaemia of previously unknown origin. METHODS Consecutive patients with chronic iron-deficient anaemia (IDA) with H. pylori infection and a negative standard work-up were prospectively evaluated. All of them had either iron refractoriness or iron dependency. Response to H. pylori eradication was assessed at 6 and 12 mo from follow-up. H. pylori infection was considered to be the cause of the anaemia when a complete anaemia resolution without iron supplements was observed after eradication. RESULTS H. pylori was eradicated in 88 of the 89 patients. In the non-eradicated patient the four eradicating regimens failed. There were violations of protocol in 4 patients, for whom it was not possible to ascertain the cause of the anaemia. Thus, 84 H. pylori eradicated patients (10 men; 74 women) were available to assess the effect of eradication on IDA. H. pylori infection was considered to be the aetiology of IDA in 32 patients (38.1%; 95%CI: 28.4%-48.8%). This was more frequent in men/postmenopausal women than in premenopausal women (75% vs 23.3%; P < 0.0001) with an OR of 9.8 (95%CI: 3.3-29.6). In these patients, anaemia resolution occurred in the first follow-up visit at 6 mo, and no anaemia or iron deficiency relapse was observed after a mean follow-up of 21 ± 2 mo. CONCLUSION Gastric H. pylori infection is a frequent cause of iron-refractory or iron-dependent anaemia of previously unknown origin in adult patients.

Intestinal Intraepithelial Lymphocyte Cytometric Pattern Is More Accurate than Subepithelial Deposits of Anti-Tissue Transglutaminase IgA for the Diagnosis of Celiac Disease in Lymphocytic Enteritis

Background & Aims An increase in CD3+TCRγδ+ and a decrease in CD3− intraepithelial lymphocytes (IEL) is a characteristic flow cytometric pattern of celiac disease (CD) with atrophy. The aim was to evaluate the usefulness of both CD IEL cytometric pattern and anti-TG2 IgA subepithelial deposit analysis (CD IF pattern) for diagnosing lymphocytic enteritis due to CD. Methods Two-hundred and five patients (144 females) who underwent duodenal biopsy for clinical suspicion of CD and positive celiac genetics were prospectively included. Fifty had villous atrophy, 70 lymphocytic enteritis, and 85 normal histology. Eight patients with non-celiac atrophy and 15 with lymphocytic enteritis secondary to Helicobacter pylori acted as control group. Duodenal biopsies were obtained to assess both CD IEL flow cytometric (complete or incomplete) and IF patterns. Results Sensitivity of IF, and complete and incomplete cytometric patterns for CD diagnosis in patients with positive serology (Marsh 1+3) was 92%, 85 and 97% respectively, but only the complete cytometric pattern had 100% specificity. Twelve seropositive and 8 seronegative Marsh 1 patients had a CD diagnosis at inclusion or after gluten free-diet, respectively. CD cytometric pattern showed a better diagnostic performance than both IF pattern and serology for CD diagnosis in lymphocytic enteritis at baseline (95% vs 60% vs 60%, p = 0.039). Conclusions Analysis of the IEL flow cytometric pattern is a fast, accurate method for identifying CD in the initial diagnostic biopsy of patients presenting with lymphocytic enteritis, even in seronegative patients, and seems to be better than anti-TG2 intestinal deposits.

Mild enteropathy as a cause of iron-deficiency anaemia of previously unknown origin

BACKGROUND AND AIMS We assessed whether mild enteropathy with negative coeliac serology may be gluten-dependent, and a cause of iron-deficiency anaemia. In cases not responding to gluten-free diet, the role of Helicobacter pylori infection was evaluated. METHODS 55 consecutive unexplained iron-deficiency anaemia patients were included. In all of them we performed: HLA-DQ2/DQ8 coeliac genetic study, distal duodenum biopsies, and tests to assess H. pylori infection. A gluten-free diet or H. pylori eradication was used as indicated. Final diagnosis was established based on response to specific therapy after a 12-month follow-up period. RESULTS Histological findings were: (1) group A (positive genetics): 21 Marsh I, 2 Marsh IIIA, 12 normal; (2) group B (negative genetics): 16 Marsh I, 4 normal. Final diagnosis of anaemia in patients with enteropathy were: group A, gluten-sensitive enteropathy, 45%; H. pylori infection, 20%; gluten-sensitive enteropathy plus H. pylori, 10%; other, 10%; unknown, 15%; group B, gluten-sensitive enteropathy, 10%; H. pylori infection, 0% (1 non-eradicated case, 10%); non-steroidal anti-inflammatory drug intake, 20%; other, 20%; unknown, 40% (p=0.033). CONCLUSIONS Mild enteropathy is frequent in patients with unexplained iron-deficiency anaemia and negative coeliac serology. Most cases are secondary to either gluten-sensitive enteropathy or H. pylori infection, or both; however, there is also a substantial number of patients without a definitive diagnosis.

Transcultural adaptation and validation of the Celiac Disease Quality of Life (CD-QOL) survey, a specific questionnaire to measure quality of life in patients with celiac disease

INTRODUCTION celiac disease is a chronic condition that requires continued treatment, with the resultant impact on health-related quality of life (HRQOL) of people who suffer it. Most studies in this field have used generic questionnaires to measure HRQOL in celiac patients. It was therefore decided to conduct a study to translate into Spanish and validate a specific questionnaire for celiac disease, the Celiac Disease Quality Of Life Survey (CD-QOL). OBJECTIVES to translate and validate in Spanish the specific celiac disease questionnaire CD-QOL. METHODS a multicenter, prospective, observational study was designed consisting of two phases: In the first phase, the questionnaire was translated and adapted into Spanish using the translation/back translation procedure and an understandability study. In the second phase, internal consistency of the translated questionnaire was analyzed. For this, results of the CD-QOL were compared to those of EuroQol and the Daily Fatigue Impact Scale (D-FIS). Understandability of the translated and adapted questionnaire was tested in six patients, and the validation study was done in 298 celiac patients (201 treated with a gluten-free diet and 97 at diagnosis). RESULTS in both celiac groups, Cronbach´s alpha coefficient was high (0.90), feasibility was excellent (99.2 % of patients completed all questions), and there were no ceiling and floor effects. Spearman correlation to EuroQol and D-FIS was statistically significant (p < 0.05). CD-QOL score was different depending on whether state of health was good, fair, or poor based on the EuroQol score. CONCLUSION the Spanish version of the CD-QOL is a valid tool for measuring HRQOL in celiac patients.

Double-Blind Randomized Clinical Trial: Gluten versus Placebo Rechallenge in Patients with Lymphocytic Enteritis and Suspected Celiac Disease

Background The role of gluten as a trigger of symptoms in non-coeliac gluten sensitivity has been questioned. Aim To demonstrate that gluten is the trigger of symptoms in a subgroup of patients fulfilling the diagnostic criteria for non-coeliac gluten sensitivity (NCGS), which presented with lymphocytic enteritis, positive celiac genetics and negative celiac serology. Methods Double-blind randomized clinical trial of gluten vs placebo rechallenge. Inclusion criteria: >18 years of age, HLA-DQ2/8+, negative coeliac serology and gluten-dependent lymphocytic enteritis, and GI symptoms, with clinical and histological remission at inclusion. Eighteen patients were randomised: 11 gluten (20 g/day) and 7 placebo. Clinical symptoms, quality of life (GIQLI), and presence of gamma/delta+ cells and transglutaminase deposits were evaluated. Results 91% of patients had clinical relapse during gluten challenge versus 28.5% after placebo (p = 0.01). Clinical scores and GIQLI worsened after gluten but not after placebo (p<0.01). The presence of coeliac tissue markers at baseline biopsy on a gluten-free diet allowed classifying 9 out of the 18 (50%) patients as having probable ‘coeliac lite’ disease. Conclusion This proof-of-concept study indicates that gluten is the trigger of symptoms in a subgroup of patients fulfilling the diagnostic criteria for NCGS. They were characterized by positive celiac genetics, lymphocytic enteritis, and clinical and histological remission after a gluten-free diet. Trial Registration ClinicalTrials.gov NCT02472704

Immunological Differences between Lymphocytic and Collagenous Colitis.

BACKGROUND Lymphocytic (LC) and collagenous (CC) colitis are the two major forms of microscopic colitis (MC). The aim of this study was to identify similarities and differences in their mucosal immune characteristics. METHODS Colonic biopsies from 15 CC, 8 LC, and 10 healthy controls were collected. Mucosal lymphocytes were assessed by flow cytometry. Tissue gene expression and protein levels were determined by real-time PCR and ELISA, respectively. RESULTS LC patients had lower numbers of CD4(+) and double-positive CD4(+)CD8(+)mucosal T lymphocytes, and higher numbers of CD8(+) and CD4(+)TCRγδ(+) mucosal T cells, compared with controls and CC patients. Regulatory Treg (CD4(+)CD25(+)FOXP3(+)) and double-negative (CD3(+)CD4(-)CD8(-)) T cell percentages were higher in both CC and LC compared with controls, coupled with higher levels of the anti-inflammatory IL-10, both at mRNA and protein levels. By contrast, Th1 and Th17 cells were lower in both CC and LC, although gene expression of Th1/Th17 cytokines was higher in both. CONCLUSION CC and LC share some regulatory and effector mechanisms, but not others. Higher IL-10 levels and higher Treg and double-negative T cell percentages, found in both CC and LC, could be responsible for the lack of progression of structural damage and the blockade of proinflammatory cytokine production. However, CC and LC are revealed as separate, independent entities, as they show clearly different mucosal lymphocyte profiles, which could be caused by different luminal triggers of the two diseases. Hence, CC and LC are two closely related but independent intestinal disorders.

Enterococcus gallinarum bacteriascites in a patient with active tuberculosis and HCV cirrhosis

TO THE EDITOR: In the January issue, Maxwell et al. (1) describe an intriguing relationship between the use of antibiotics and the development of functional bowel symptoms likened to irritable bowel syndrome (IBS). They determined that in their cohort of subjects, 4 months after the use of antibiotics, there was an increased incidence of functional GI symptoms relative to controls. There are, however, some concerns with the study, and the authors may have overlooked other interpretations of their data. First, the authors provide background to suggest that when infectious diarrhea is treated with antibiotics, the incidence of IBS symptoms is higher (82%) than in controls (68%), based on a study by Gwee et al. (2). What is not adequately quoted is that this difference was not significant and that it likely represented a more severe infectious illness in the IBS group. In fact, the reported degree of diarrhea and abdominal pain during the infectious illness was higher among those subjects who ultimately developed IBS and likely determined the increased (albeit not significantly) level of antibiotic use. Another concern about Maxwell and colleagues’ article is the timing of their questionnaire (1). Clearly, it was first administered after the subjects had already received the antibiotics. Although there appeared to be a similar preantibiotic prevalence of IBS described in Table 1, there also appeared to be a lower median number of functional symptoms in the preceding month in antibiotic-treated subjects versus controls (0.5 vs 2.0). The authors later describe results suggesting that at the time of the first questionnaire (after antibiotics) more IBS subjects had no functional symptoms. In fact, 50% of antibiotic-treated subjects reported no functional bowel symptoms, compared with 33% of the controls (p 0.09). Four months after antibiotic use this trend reversed but was more statistically equal to controls (p 0.2). Based on these results, the authors need at least to consider the possibility that the antibiotic use may have initially diminished functional symptoms, with return/ exacerbation of these symptoms 4 months later. There are a number of ways the authors could have sorted this out. First, they could have administered a questionnaire just before the use of antibiotics in addition to immediately after. Second, they could track the initial bowel habits (e.g., the 1st wk after antibiotics) and again compare bowel symptoms to controls to determine if there was an initial detrimental or beneficial effect of treatment. Third, the course of symptoms could have been tracked over time. Why was 4 months chosen? Why would there be less IBS symptoms initially upon completion of antibiotics and yet a worsening later? This needs to be discussed. There are other data supporting this alternative explanation whereby antibiotics may produce a beneficial effect in IBS. The first is an article by Nayak et al. (3) suggesting that metronidazole given in a double-blind placebo-controlled fashion actually improved IBS symptoms in subjects relative to controls. The second is an article by our group (4) suggesting a role of intestinal flora in IBS whereby antibiotics resulted in a significant improvement of IBS symptoms. Although both studies are recognized to have their limitations, the authors fail to discuss this possibility and have not adequately ruled it out. Despite the criticisms, this article is important, as it again hints at the potential relationship between functional symptoms and enteric bacteria as influenced by antibiotics. We look forward to any follow-up studies the authors have that may rule in or out any initial beneficial effects of antibiotics as a confounding factor.