Contributions of HLA haplotypes, IL8 level and Toxoplasma gondii infection in defining celiac disease's phenotypes.

BACKGROUND: It is not clear why some patients with coeliac disease (CD) present with severe symptoms and small intestinal mucosal damages while others present with milder symptoms and no frank enteropathy. There is no study to assess the associated factors with mild/severe symptoms and enteropathy. The terminologies like latent, silent and potential are difficult to use and are unrepresentative. In the present study we describe coeliac disease's phenotypes based on HLA haplotypes, IL8 production and past infection with Toxoplasma gondii (T. gondii) infection. METHODS: In this case-control study, sera originating from 150 healthy subjects and 150 patients diagnosed with CD during the years 2013-14 were analyzed for the presence of antibodies specific T. gondii of the IgG and IgM subclasses. The level of IL8 were measured and HLA-DQ2 and HLA-DQ8 alleles were genotyped. The correlation between these parameters and the damages in intestinal mucosal were assessed using an accepted histopathological classification. RESULTS: High levels of IgG antibodies against T. gondii were found in the sera of control group compared to the CD group (52.6% vs. 39.4%, P = 0.02). Mean serum levels of IL8 was significantly higher in CD patients compared with control (P ≤ 0.05). By comparing the level of anti- T. gondii IgG and mucosal damage in celiac disease, we found a significant relationship between the severity of mucosal damages and anti- T. gondii IgG level (P = 0.02). No correlation was detected between Toxoplasma gondii infection and types of HLA (P > 0.05). However, patients with severely abnormal histology carried HLA-DQ2 risk alleles (92 patients (61%)) more often than the controls and those with mild histological abnormalities. CONCLUSIONS: CD patients with severe histological changes had more often Toxoplasma gondii infection than those affected with mild histological features. This suggests that CD's phenotypes are correlated to additional factors like infections and to particular HLA DQ2 alleles that may need additional investigations and potentially will require additional treatment.

Immunogenetic Pathogenesis of Celiac Disease and Non-celiac Gluten Sensitivity.

Celiac disease is the most common oral intolerance in Western countries. It results from an immune response towards gluten proteins from certain cereals in genetically predisposed individuals (HLA-DQ2 and/or HLA-DQ8). Its pathogenesis involves the adaptive (HLA molecules, transglutaminase 2, dendritic cells, and CD4(+) T-cells) and the innate immunity with an IL-15-mediated response elicited in the intraepithelial compartment. At present, the only treatment is a permanent strict gluten-free diet (GFD). Multidisciplinary studies have provided a deeper insight of the genetic and immunological factors and their interaction with the microbiota in the pathogenesis of the disease. Similarly, a better understanding of the composition of the toxic gluten peptides has improved the ways to detect them in food and drinks and how to monitor GFD compliance via non-invasive approaches. This review, therefore, addresses the major findings obtained in the last few years including the re-discovery of non-celiac gluten sensitivity.

Segmental pneumatosis cystoides coli: computed tomography-facilitated diagnosis.

Intestinal pneumatosis is a rare entity of unclear etiopathogenesis characterized by the presence of gaseous cystic or linear collections within the intestinal wall. Intestinal pneumatosis may be primary and idiopathic in origin or, more frequently, it accompanies various clinical conditions. Rarely, the development of intestinal pneumatosis is attributed to the pharmacotherapy with different drugs. This is a case report of cystic pneumatosis limited to the large intestine with predominant clinical presentation of chronic watery diarrhea in a 64-year-old man suffering from diabetes mellitus treated with metformin and acarbose. The patient had been referred to the outpatient gastroenterology clinic for further investigation of numerous polyp-like lesions found on colonoscopy. There was no history of cigarette smoking, drug abuse or extraintestinal complaints. The patient was in a good general condition and his laboratory tests were normal. No relevant abnormalities were found on chest X-ray, esophagogastroduodenoscopy or abdominal ultrasound, but computed tomography showed intramural gas-filled bubbles in the cecum and splenic flexure without signs of perforation or any other significant pathology in the abdominal cavity. The final diagnosis of pneumatosis cystoides coli (PCC), possibly related to treatment with acarbose, was established. On a follow-up visit after discontinuation of acarbose the patient reported no complaints and remained asymptomatic for the next 12 months. To conclude, drug-related PCC should be considered in a differential diagnosis of gastrointestinal symptoms and/or polyp-like lesions disclosed on colonoscopy in diabetic patients treated with acarbose.

Central America in Transition: From Maize to Wheat Challenges and Opportunities.

The Central American countries: Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama are in transition from a dietary culture based mainly on maize to a wheat-containing diet. Several other changes are occurring, such as a decrease of parasitic and infectious diseases. The environmental changes permit a prediction of an increase of celiac disease and other autoimmune diseases such as type I diabetes and thyroid disease in these genetically heterogeneous countries. At present, celiac disease and gluten-related disorders are considered to be of no relevance at the level of public health in these nations. This review documents the presence of celiac disease in Central America. It draws attention to some of the challenges in planning systematic studies in the region since up until recently celiac disease was unknown. The aim of this review is to disseminate knowledge obtained with preliminary data, to stimulate clinical and basic scientists to study these diseases in Central America and to alert authorities responsible for the planning of education and health, to find possibilities to avoid a rise in these disorders before the epidemics start, as has occurred in the Mediterranean countries.

Abdominal splenosis.

Splenosis is a benign condition caused by an ectopic autotransplantation of splenic tissues after splenic trauma or surgery. It usually occurs within the abdominal and pelvic cavity. Patients are generally asymptomatic and this entity is diagnosed accidentally. However, occasionally extensive abdominal splenosis poses a significant diagnostic dilemma for gastroenterologists, especially when this condition manifests as a disseminated metastatic malignant disease on abdominal imaging.This paper presents a concise review of the literature on this often misleading disorder. The crucial role of taking a thorough patient´s medical history concerning splenic trauma in the past, the need for differential diagnosis of tumor-like lesions disclosed on abdominal imaging and novel diagnostics modalities that allow avoiding unnecessary laparotomy in case of abdominal splenosis are stressed.The increased prevalence of abdominal trauma due to road accidents and the growing armamentarium of available imaging modalities suggest that abdominal splenosis may be expected more often than ever.In order to prevent any possible diagnostic doubts and unnecessary future invasive examinations, confirmed splenosis should be recorded in the medical documentation of the patient.

Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease.

AIM: To investigate the effect of vitamin supplements on homocysteine levels in patients with celiac disease. METHODS: Vitamin B6, folate, vitamin B12, and fasting plasma homocysteine levels were measured in 51 consecutive adults with celiac disease [median (range) age 56 (18-63) years; 40% men, 26 (51%) had villous atrophy, and 25 (49%) used B-vitamin supplements] and 50 healthy control individuals matched for age and sex. Finally, the C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) was evaluated in 46 patients with celiac disease and all control individuals. RESULTS: Patients with celiac disease and using vitamin supplements had higher serum vitamin B6 (P = 0.003), folate (P < 0.001), and vitamin B12 (P = 0.012) levels than patients who did not or healthy controls (P = 0.035, P < 0.001, P = 0.007, for vitamin B6, folate, and vitamin B12, respectively). Lower plasma homocysteine levels were found in patients using vitamin supplements than in patients who did not (P = 0.001) or healthy controls (P = 0.003). However, vitamin B6 and folate, not vitamin B12, were significantly and independently associated with homocysteine levels. Twenty-four (48%) of 50 controls and 23 (50%) of 46 patients with celiac disease carried the MTHFR thermolabile variant T-allele (P = 0.89). CONCLUSION: Homocysteine levels are dependent on Marsh classification and the regular use of B-vitamin supplements is effective in reduction of homocysteine levels in patients with celiac disease and should be considered in disease management.

Indications and challenges of probiotics, prebiotics, and synbiotics in the management of arthralgias and spondyloarthropathies in inflammatory bowel disease.

Arthralgia and spondyloarthropathy of the peripheral and the axial joints are common in patients with inflammatory bowel diseases. Evidence for this association has been provided by clinical, epidemiologic, and immunologic studies confirming the presence of shared inflammatory pathways in gut and joint. Bacterial gut infections such as Salmonella typhimurium, Yersinia enterocolitica, Shigella, Campylobacter jejuni may induce reactive peripheral arthritis and 20% of these patients may develop chronic spondyloarthropathy. It is not certain that arthralgias in inflammatory bowel diseases are more frequent than in the general population but clinical articular manifestations compatible with spondyloarthropathy are present in 10% to 40% of patients with inflammatory bowel diseases. These enteropathic peripheral arthropathies without axial involvement are subdivided into a pauciarticular of large joints and a bilateral symmetrical polyarthropathy. The rationale and the challenges of using prebiotics, probiotics, and synbiotics in the management of patients with inflammatory bowel diseases with arthralgias and spondyloarthropathy are briefly reviewed. The rationale is based on the modulation of the ubiquitous intestinal flora by bacteria and their products that have been proven to be safe. The challenge is to find the "window of opportunity" to treat the evolutionary stage of joint inflammation. It seems to us that the major aim is not to treat patients who have a self-limited inflammatory joint disorder, but those patients with persistent arthralgias in an early phase of the disease. Seronegative and seropositive patients with early arthritis, before damage may occur, could be managed by this approach to improve the quality of life and to positively influence the natural course of the disease.

N-acetyl-L-cysteine combined with mesalamine in the treatment of ulcerative colitis: randomized, placebo-controlled pilot study.

AIM: To evaluate the effectiveness and safety of oral N-acetyl-L-cysteine (NAC) co-administration with mesalamine in ulcerative colitis (UC) patients. METHODS: Thirty seven patients with mild to moderate UC were randomized to receive a four-wk course of oral mesalamine (2.4 g/d) plus N-acetyl-L-cysteine (0.8 g/d) (group A) or mesalamine plus placebo (group B). Patients were monitored using the Modified Truelove-Witts Severity Index (MTWSI). The primary endpoint was clinical remission (MTWSI < or = 2) at 4 wk. Secondary endpoints were clinical response (defined as a reduction from baseline in the MTWSI of > or = 2 points) and drug safety. The serum TNF-alpha, interleukin-6, interleukin-8 and MCP-1 were evaluated at baseline and at 4 wk of treatment. RESULTS: Analysis per-protocol criteria showed clinical remission rates of 63% and 50% after 4 wk treatment with mesalamine plus N-acetyl-L-cysteine (group A) and mesalamine plus placebo (group B) respectively (OR = 1.71; 95% CI: 0.46 to 6.36; P = 0.19; NNT = 7.7). Analysis of variance (ANOVA) of data indicated a significant reduction of MTWSI in group A (P = 0.046) with respect to basal condition without significant changes in the group B (P = 0.735) during treatment. Clinical responses were 66% (group A) vs 44% (group B) after 4 wk of treatment (OR = 2.5; 95% CI: 0.64 to 9.65; P = 0.11; NNT = 4.5). Clinical improvement in group A correlated with a decrease of IL-8 and MCP-1. Rates of adverse events did not differ significantly between both groups. CONCLUSION: In group A (oral NAC combined with mesalamine) contrarily to group B (mesalamine alone), the clinical improvement correlates with a decrease of chemokines such as MCP-1 and IL-8. NAC addition not produced any side effects.

Retrospective analysis of old-age colitis in the Dutch inflammatory bowel disease population.

AIM: To describe the characteristics of Dutch patients with chronic inflammatory bowel disease (IBD) first diagnosed above 60 years of age-a disease also known as old-age colitis (OAC) and to highlight a condition that has a similar appearance to IBD, namely segmental colitis associated with diverticular disease (SCAD). METHODS: A retrospective longitudinal survey of patient demographic and clinical characteristics, disease characteristics, diagnostic methods, management and course of disease was performed. The median follow-up period was 10 years. RESULTS: Of a total of 1100 IBD patients attending the Department of Gastroenterology, 59 (5%) [median age 82 years (range 64-101); 25 male (42%)] were identified. These patients were diagnosed with ulcerative colitis (n = 37, 61%), Crohn's disease (n = 14, 24%), and indeterminate colitis (n = 8, 15%). Remission was induced in 40 (68%) patients within a median interval of 6 mo (range 1-21) and immunosuppressive therapy was well tolerated. Histological evaluation based on many biopsy samples and the course of the disease led to other diagnosis, namely SCAD instead of IBD in five (8%) patients. CONCLUSION: OAC is not an infrequent problem for the gastroenterologist, and should be considered in the evaluation of older patients with clinical features suggestive of IBD. Extra awareness and extensive biopsy sampling are required in order to avoid an erroneous diagnosis purely based on histological mimicry of changes seen in SCAD, when diagnosing IBD in the presence of diverticulosis coli.

Coeliac disease in Dutch patients with Hashimoto's thyroiditis and vice versa.

AIM: To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patients. METHODS: A total of 104 consecutive patients with Hashimoto's thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies). RESULTS: Of 104 patients with Hashimoto's thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or -DQ8) was present in all the five and 53 patients with Hashimoto's thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassified into euthyroidism in ten (5%; 95% CI 2-9), subclinical hypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto's thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves' disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis. CONCLUSION: The data from a Dutch population confirm the association between Hashimoto's thyroiditis and coeliac disease. Screening patients with Hashimoto's thyroiditis for coeliac disease and vice versa is recommended.

Reviewing the mechanism of action of thiopurine drugs: towards a new paradigm in clinical practice.

The precise mechanism of action of thiopurine drugs remains unclear despite more than 40 years of use. Recent knowledge in the field of apoptosis and a better insight into, as well as a rapid increase in their use in several important areas of clinical medicine justify this appraisal. This is a review of the recent advances in the knowledge of their mechanism of action and is primarily intended to help clinicians understand the pharmacological properties of these drugs adequately and to find ways to improve their use in clinical practice. The parent compound is azathioprine (AZA), which is rapidly reduced in the presence of glutathione to 6-mercaptopurine (6-MP) and then metabolized into active metabolites with immune-modifier activity. Recent observations and new data indicate that AZA/6-MP could be considered as a "two-in-one" drug, providing a source of 6-thioguanine nucleotides (6-TGNs) and methylated metabolites, and that both compounds could contribute to its antiproliferative effects. This review will also focus on mechanisms that may help to explain a number of recent observations showing that myelotoxicity may occur in patients with high TPMT level or low 6-TGN rate. Our final proposal suggests that the immunosuppressive effects of these drugs are due to a balanced combination of antimetabolic and pro-apoptotic actions.

Evaluation of oral budesonide in the treatment of active distal ulcerative colitis.

Budesonide, a topical corticosteroid, has proven useful for the management of Crohn's disease. Its efficacy is similar to prednisone but it has fewer side effects. A new pH-modified release capsule (Budenofalk) is probably efficacious in distal ulcerative colitis. The aim of the present study was to establish the pharmacokinetics, pharmacodynamics, and safety of two dosage regimens of budesonide capsules and to obtain efficacy information. Budenofalk 9 mg daily was administered as a single dose 9 mg in 8 patients and as three 3 mg doses in 7 patients with active distal ulcerative colitis for 8 weeks. Symptoms were assessed at three timepoints during the study: baseline, 4 and 8 weeks after start of treatment. Endoscopic evaluation and budesonide concentration in mucosal biopsy specimens was performed at 0 and 8 weeks. A pharmacokinetic profile and pharmacodynamic profile (cortisol, lymphocytes and neutrophils) was performed at day 5. In the 9 mg o.d. group, higher peak concentrations and systemic availability was found compared to the 3 mg t.i.d. group. Cortisol suppression was more pronounced after 9 mg o.d. than after 3 mg t.i.d. Lag-time, AUC and pharmacodynamic effects were comparable (14% mean decrease lymphocyte count and 26% mean increase neutrophil count). Mucosal biopsy specimens in the distal colon revealed significant budesonide levels with both regimens. After 8 weeks, 71% in the 9 mg o.d. group and 38% in the 3 t.i.d. group responded. The endoscopic index improved from 10 +/- 2 to 2 +/- 3 (p <0.001) with 9 mg o.d. and from 9 +/- 2 to 4 +/- 4.7 (p = 0.02) with 3 mg t.i.d. The pharmacokinetic and pharmacodynamic profiles found in this study indicate that Budenofalk reaches the distal part of colon and rectum, but further studies to validate the budesonide assay in the mucosa and comparison with a control group are necessary. This limited study suggests that Budenofalk is effective in distal colitis and side effects are rare. Based on these observations a large clinical trial using 9 mg o.d. is indicated to confirm efficacy and assess further possible side effects.

The therapeutic spectrum of infliximab and tumor necrosis factor immunomodulation in chronic inflammatory diseases.

This review summarizes the clinical results of Infliximab for the treatment of Crohn's disease, the limited data of its use in other digestive disorders and disorders related to the gastrointestinal tract. The etiology of these disorders remains enigmatic. As long as the precise etiology remains unknown, therapeutic options to treat these patients are predominantly symptomatic (i.e., immunosuppressive drugs or surgical intervention). To be able to develop more rational therapeutic regimens, it is pivotal to understand the immunopathological events that lead to, or are involved in, the pathogenesis of these diseases. Therefore, we also briefly summarize what at the present is known in this respect.