Montserrat Alsina

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.

Spectrum of gluten-sensitive enteropathy in first-degree relatives of patients with coeliac disease: clinical relevance of lymphocytic enteritis.

Background: Limited data on a short series of patients suggest that lymphocytic enteritis (classically considered as latent coeliac disease) may produce symptoms of malabsorption, although the true prevalence of this situation is unknown. Serological markers of coeliac disease are of little diagnostic value in identifying these patients. Aims: To evaluate the usefulness of human leucocyte antigen-DQ2 genotyping followed by duodenal biopsy for the detection of gluten-sensitive enteropathy in first-degree relatives of patients with coeliac disease and to assess the clinical relevance of lymphocytic enteritis diagnosed with this screening strategy. Patients and methods: 221 first-degree relatives of 82 DQ2+ patients with coeliac disease were consecutively included. Duodenal biopsy (for histological examination and tissue transglutaminase antibody assay in culture supernatant) was carried out on all DQ2+ relatives. Clinical features, biochemical parameters and bone mineral density were recorded. Results: 130 relatives (58.8%) were DQ2+, showing the following histological stages: 64 (49.2%) Marsh 0; 32 (24.6%) Marsh I; 1 (0.8%) Marsh II; 13 (10.0%) Marsh III; 15.4% refused the biopsy. 49 relatives showed gluten sensitive enteropathy, 46 with histological abnormalities and 3 with Marsh 0 but positive tissue transglutaminase antibody in culture supernatant. Only 17 of 221 relatives had positive serological markers. Differences in the diagnostic yield between the proposed strategy and serology were significant (22.2% v 7.2%, p<0.001). Relatives with Marsh I and Marsh II–III were more often symptomatic (56.3% and 53.8%, respectively) than relatives with normal mucosa (21.1%; p = 0.002). Marsh I relatives had more severe abdominal pain (p = 0.006), severe distension (p = 0.047) and anaemia (p = 0.038) than those with Marsh 0. The prevalence of abnormal bone mineral density was similar in relatives with Marsh I (37%) and Marsh III (44.4%). Conclusions: The high number of symptomatic patients with lymphocytic enteritis (Marsh I) supports the need for a strategy based on human leucocyte antigen-DQ2 genotyping followed by duodenal biopsy in relatives of patients with coeliac disease and modifies the current concept that villous atrophy is required to prescribe a gluten-free diet.

Predisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis.

Objective To assess the presence of both genetic and serological markers of coeliac disease in patients with microscopic colitis, and whether there was associated enteropathy. Methods HLA-DQ2, HLA-DQ8, serum immunoglobulin A-antiendomysial and immunoglobulin A-anti-tissue transglutaminase antibodies were investigated in 59 patients with microscopic colitis. Seventy healthy subjects acted as the control group. Endoscopic biopsies from the distal duodenum were obtained in DQ2-positive or DQ8-positive patients. Patients with histological changes compatible with gluten-sensitive enteropathy were started on a gluten-free diet. Results Seventeen of 70 (24.3%) healthy controls were DQ2-positive. Twelve of 25 (48%) patients with lymphocytic colitis (P=0.027 versus controls), and 11 of 34 (32.3%) with collagenous colitis (P=0.38 versus controls) were DQ2-positive. There were no differences in the frequency of DQ8-positivity. The coeliac serology was positive in one patient. Duodenal biopsies were performed in 23 DQ2-positive and/or DQ8-positive patients. None had villous atrophy (Marsh III lesion) (0%; 95% confidence interval, 0–6.1). A Marsh type I lesion was found in four patients. Three of these patients were put on a gluten-free diet with disappearance of diarrhoea. Conclusions The results suggest that there is an association of lymphocytic colitis with HLA-DQ2 genes, which might be relevant in the pathogenesis of this disease. The association of microscopic colitis with Marsh type III coeliac disease seems to be rare, making it unnecessary to routinely screen for coeliac disease in microscopic colitis patients.

The prevalence of coeliac disease is significantly higher in children compared with adults.

Background  Some limited studies of coeliac disease have shown higher frequency of coeliac disease in infancy and adolescence than in adulthood. This finding has remained unnoticed and not adequately demonstrated.

Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

ABSTRACT Bacterial alveolar invasion is followed by an inflammatory response. A systemic extension of the compartmentalized immune response has been described in patients with severe pneumonia. The data suggest that some antimicrobials may induce a differential release of cytokines. We conducted a prospective, randomized study in adult patients with severe pneumococcal pneumonia to measure the effects of ceftriaxone and levofloxacin in the systemic cytokine expression over time. Demographic, clinical characteristics, and severity scores were recorded. The serum concentrations of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and IL-1 receptor agonist were measured at 0, 24, 72, and 120 h. A total of 32 patients were included in the study. Both groups were homogeneous in terms of age, comorbidities, severity of disease, and corticosteroid or statin use. With the single exception of IL-1β, all cytokines were detected in venous blood. All of the cytokines studied showed a similar pattern of progressive decrease over time. No significant differences in the concentrations of any of the cytokines studied were found, with the exception of TNF-α, for which lower concentrations were obtained at 120 h in the levofloxacin group (P = 0.014). Basal oxygen saturation (P = 0.034) and heart rate (P = 0.029) returned to normal values earlier in the levofloxacin arm. We demonstrated that in patients with severe pneumococcal pneumonia pro- and anti-inflammatory responses could be detected in venous blood, representing a systemic extension of the compartmentalized response. Treatment with a β-lactam agent or a fluoroquinolone has different effects on cytokine production and its systemic expression, impacting the clinical course of the disease.

Diagnostic value of duodenal antitissue transglutaminase antibodies in gluten-sensitive enteropathy

Background  In gluten‐sensitive enteropathy, antitissue transglutaminase antibodies are synthesized in the duodenum.

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.

Are positive serum-IgA-tissue-transglutaminase antibodies enough to diagnose coeliac disease without a small bowel biopsy? Post-test probability of coeliac disease

BACKGROUND It has been suggested that high titres of tTG are associated with elevated positive predictive values (PPV) for celiac disease. However, the PPV of a strongly positive tTG will depend on the celiac disease prevalence in the different risk groups of the disease AIMS To assess the PPV of a strongly positive tTG for celiac disease. In addition, to calculate the post-test probability for celiac disease of a strongly positive tTG in a setting of routine clinical practice. METHODS 145 consecutive celiac disease patients with positive tTG, and with a small bowel biopsy were included. The PPV for different cut-off points of tTG levels for the diagnosis of celiac disease was assessed. In addition, the cut-offs associated with higher PPV were used to calculate the positive likelihood ratio. A simulation in a setting of routine clinical practice was performed to calculate the post-test probability of celiac disease. RESULTS No cut-off level was associated with a PPV of 100%. A cut-off of 80 U/mL (11.4×upper normal limit) was associated with the higher PPV value of 98.6%. In the most frequent clinical situations, which in general have a pre-test probability <10%, the post-test probability after having a strongly positive tTG was 90% or less. CONCLUSIONS A strongly positive tTG should not be enough to diagnose celiac disease in the most frequent clinical situations, small bowel biopsy remaining as the gold standard in these cases.

Prevalence and clinical relevance of enteropathy associated with systemic autoimmune diseases

OBJECTIVE To assess whether systemic autoimmune diseases are a risk group for coeliac disease and if there is a systemic autoimmune diseases-associated enteropathy. METHODS 183 patients with systemic autoimmune diseases were included. Duodenal biopsy was carried out on patients with positive coeliac genetics (HLA-DQ2-DQ8) and/or serology and/or symptoms of the coeliac disease spectrum. When enteropathy was found, causes, including gluten sensitivity, were investigated and categorized according to a sequentially applied treatment. Results were analysed with Chi-square or Fisher exact tests. RESULTS The prevalence of coeliac disease with atrophy was 0.55% (1 of 183 patients). Thirty-eight of the 109 patients (34.8%) who underwent duodenal biopsy had lymphocytic enteropathy (8 infectious, 5 due to gluten sensitive enteropathy, 5 HLA-DQ2/DQ8 who did not accept gluten-free diet and 20 of unknown aetiology). Lymphocytic enteropathy was unrelated to disease activity or immunosuppressants. HLA-DQ2 was more frequent in connective tissue disease (41.5%) compared with systemic vasculitis and autoinflammatory diseases (17.9%) (p=0.02), whereas a lower percentage of lymphocytic enteropathy was observed in the former (20.2% vs. 41.6%). Lymphocytic enteropathy was clinically irrelevant in cases with no definite aetiology. DISCUSSION One third of systemic autoimmune diseases patients had enteropathy of uncertain clinical meaning in the majority of cases, which was rarely due to gluten sensitive enteropathy.