A Cross-Sectional Study of the Prevalence of Gastrointestinal Symptoms and Pathology in Patients With Common Variable Immunodeficiency.

OBJECTIVES: The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation. METHODS: In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163). Microarray analysis compared "celiac-like disease" in CVID to celiac disease. Screening for selected bacterial and viral infections in fecal samples and gut mucosal biopsies was performed. RESULTS: The main findings of this study were as follows: most common GI symptoms were bloating (34%), pain (30%), and diarrhea (26%). The most frequent histopathological findings were increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., "celiac-like disease" (46% of patients), decreased numbers of plasma cells in GI tract mucosa (62%), and lymphoid hyperplasia (38%), none of which were associated with GI symptoms. Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics of CVID, and increased serum levels of sCD14 (P=0.025), sCD25 (P=0.01), and sCD163 (P=0.04). Microarray analyses distinguished between CVID patients with "celiac-like disease" and celiac disease. Positive tests for bacterial and viral infections were scarce both in fecal samples and gut mucosal biopsies, including PCR test for norovirus in biopsy specimens (0 positive tests). CONCLUSIONS: In conclusion, GI pathology is common in CVID, but does not necessarily cause symptoms. However, reduced plasma cells in GI mucosa were linked to systemic immune activation, "celiac-like disease" in CVID and true celiac disease appear to be different disease entities, as assessed by gene expression, and infections (including norovirus) are rarely a cause of the CVID enteropathy.

Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity.

OBJECTIVES: In celiac disease (CD), gluten induces both adaptive and innate immune responses. Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the immune response is less characterized. The aim of our study was to explore and compare the early mucosal immunological events in CD and NCGS. METHODS: We challenged 30 HLA-DQ2(+) NCGS and 15 CD patients, all on a gluten-free diet, with four slices of gluten-containing bread daily for 3 days. Duodenal biopsy specimens were collected before and after challenge. The specimens were examined for cytokine mRNA by quantitative reverse transcriptase-PCR and for MxA-expression and CD3(+) intraepithelial lymphocytes (IELs) by immunohistochemistry and compared with specimens from untreated CD patients and disease controls. RESULTS: In CD patients, tumor necrosis factor alpha (P=0.02) and interleukin 8 (P=0.002) mRNA increased after in vivo gluten challenge. The interferon gamma (IFN-γ) level of treated CD patients was high both before and after challenge and did not increase significantly (P=0.06). Four IFN-γ-related genes increased significantly. Treated and untreated CD patients had comparable levels of IFN-γ. Increased expression of MxA in treated CD patients after challenge suggested that IFN-α was activated on gluten challenge. In NCGS patients only IFN-γ increased significantly (P=0.03). mRNA for heat shock protein (Hsp) 27 or Hsp70 did not change in any of the groups. Importantly, we found that the density of IELs was higher in NCGS patients compared with disease controls, independent of challenge, although lower than the level for treated CD patients. CONCLUSIONS: CD patients mounted a concomitant innate and adaptive immune response to gluten challenge. NCGS patients had increased density of intraepithelial CD3(+) T cells before challenge compared with disease controls and increased IFN-γ mRNA after challenge. Our results warrant further search for the pathogenic mechanisms for NCGS.

Intestinal malabsorption of D-xylose: comparison of test modalities in patients with celiac disease.

OBJECTIVE: The aim of the study was to compare three different D-xylose test modalities for small intestinal malabsorption, using patients with celiac disease and healthy persons as experimental models. MATERIAL AND METHODS: Ninety-one untreated celiac patients, 98 treated celiac patients, and 43 healthy subjects performed the (13)C-D-xylose breath test. 1-h plasma D-xylose levels were measured in 48 untreated patients, 41 treated patients and 41 healthy controls. 4-h urine D-xylose excretion was measured in 47 untreated patients, 51 treated patients and 42 healthy controls. 100 mg of (13)C-D-xylose and 5 g of D-xylose were dissolved in 250 ml tap water and given orally. (13)CO(2) was measured in breath every 30 min for 4 h. Blood was sampled after 1 h, and urine collected after 4 h. RESULTS: Test sensitivity/specificity for celiac disease was 88%/84% with the (13)C-D-xylose breath test, 65%/71% with the 1-h plasma D-xylose test, and 55%/74% with the 4-h urine D-xylose excretion test. Breath test results improved significantly in the treated celiac group compared to untreated patients, but were not normalized compared to healthy controls. No difference was found between 1-h plasma D-xylose levels and 4-h urinary D-xylose excretion in treated celiac patients and healthy controls. CONCLUSIONS: The (13)C-D-xylose breath test was superior to D-xylose testing in plasma and urine for assessment of small intestinal malabsorption with considerably higher sensitivity and specificity for untreated celiac disease.

Serum nutrients and habitual dietary intake in colectomized FAP patients in Norway.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are colectomized in young age in order to avoid development of colorectal cancer. Because colectomy radically changes gastrointestinal physiology, and food avoidance may be present, colectomized patients may be at risk for nutritional deficiency. AIM OF THE STUDY: to evaluate: (1) serum biochemical levels as compared to reference; (2) dietary intake as compared to the recommendations. METHODS: Blood samples, interviews and food frequency questionnaire were collected from 38 colectomized FAP patients with duodenal adenomas (mean age 40 years, range: 24-70). They were recruited from the Norwegian database on FAP. RESULTS: Serum albumin was significantly higher (P < or = 0.0001), and Mg (P = 0.02), ferritin (P < or = 0.001), and cholesterol (P = 0.03) significantly lower, than reference levels. Compared to recommendations, a low intake was seen for folate and fiber (<50%), iron, thiamin, riboflavin (< 25%), and omega-3 fatty acids (8%). Sugar intake exceeded the recommendation, mainly due to a high intake of soft drinks. Food avoidance was reported by 53%. CONCLUSIONS: We would suggest that the nutrient intake among FAP patients should at least meet the recommendations for healthy subjects. Their risk of metachronous cancers should also cause special attention to dietary factors that may prevent nutritional deficiency and carcinogenesis.

The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder.

BACKGROUND: It has recently been hypothesized that bipolar disorders are associated with accelerated aging. Telomere dysfunction, a biomarker of aging, is determined by the load of short telomeres, rather than by the mean telomere length. To our knowledge, the load of short telomeres has not been reported in any psychiatric disorder. The aims of the study were to examine the load of short telomeres and the mean telomere length and their relationships with illness duration and lifetime number of depressive episodes in bipolar II disorder (BD-II). METHODS: Twenty-eight patients (mean age=34.8 ± 7.7) with a DSM-IV diagnosis of BD-II and 28 healthy control subjects (mean age=34.8 ± 9.2) matched for age, sex, and education participated. The load of short telomeres (percentage of telomeres <3 kilobases) and mean telomere length in peripheral blood mononuclear cells were measured using high-throughput quantitative fluorescence in situ hybridization. RESULTS: The load of short telomeres was significantly increased in patients with BD-II relative to healthy controls and may represent 13 years of accelerated aging. The load of short telomeres and the mean telomere length were associated with lifetime number of depressive episodes, but not with illness duration. LIMITATIONS: Modest sample size and cross-sectional design. CONCLUSIONS: Our results suggest that BD-II is associated with an increased load of short telomeres. Depressive episode-related stress may accelerate telomere shortening and aging. However, longitudinal studies are needed to fully clarify telomere shortening and its relationship with clinical variables in BD-II.

Selective COX-2 inhibition affects fatty acids, but not COX mRNA expression in patients with FAP.

Familial adenomatous polyposis (FAP) provides a model for sporadic colorectal cancer development. Cyclooxygenase (COX) inhibition may ameliorate polyp development, but rofecoxib was withdrawn due to cardiovascular side effects. Although this selective COX-2 inhibitor, like diet, may alter the fatty acid and eicosanoid pattern, data on the potential alteration in tissues after use, are scarce. The aims were to study if rofecoxib might influence the fatty acid distribution in serum phospholipids and duodenal lesions, mRNA for COX-1 and COX-2 in leucocytes and duodenal lesions, and finally plasma levels of PGE(2) in a randomized, double-blind, placebo controlled study (n = 38). Significant reductions were found for essential fatty acid index both in serum phospholipids (P = 0.01, 95% CI = -0.9; -0.1), and in duodenal lesions (P = 0.04, 95 CI % = -0.9; -0.1) after treatment. No treatment effects were found on the COX mRNA expression, or in the plasma PGE(2) levels. Dietary AA/EPA ratio was inversely associated with all the indicators of EFA status (all P < 0.01). These findings suggest that the effects of COX chemoprevention should be further investigated in FAP and that dietary needs should be included in the treatment of FAP.

No induction of anti-avenin IgA by oats in adult, diet-treated coeliac disease.

OBJECTIVE: Coeliac disease is effectively treated with a gluten-free diet devoid of wheat, rye, barley and related cereals. Oats has until recently also been considered harmful but is now allowed in several countries. We have, however, identified three adult coeliac disease patients who developed a flare of active coeliac disease after ingestion of oats, which suggests that oats might not be entirely innocent in coeliac disease. It is known that patients with untreated coeliac disease have elevated IgA antibodies to oat prolamins. The objective of this study was to investigate whether levels of IgA against oats were increased in treated, adult coeliac disease patients. MATERIAL AND METHODS: Serum was collected from 136 adult patients with treated coeliac disease and 139 controls. Eighty-two of the coeliac disease patients had been taking oats as part of their gluten-free diet for 6 months or more. IgA against oats avenin, wheat gliadin and tissue transglutaminase was tested with ELISA. RESULTS: No significant differences were found in IgA against oats in oats-eating and non-oats-eating coeliac disease patients. Both groups had increased levels of IgA against wheat, oats and tissue transglutaminase compared to healthy controls. A significant positive correlation was found between anti-avenin and antigliadin IgA (p<0.0001), and between anti-avenin and anti-tissue transglutaminase IgA (p=0.0012). CONCLUSIONS: Ingestion of oats does not cause increased levels of IgA against oats in adult coeliac disease patients on a gluten-free diet. The findings support the notion that most adult coeliac disease patients can tolerate oats.

Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease.

BACKGROUND & AIMS: Patients with celiac disease (CD) who do not improve or exhibit villous atrophy on a gluten-free diet may have type 1 refractory CD (RCD) with a polyclonal mucosal T-cell infiltrate, or type 2 RCD with a monoclonal infiltrate, also termed cryptic T-cell lymphoma. Both conditions are difficult to treat. Here we describe the effects of a nonimmunogenic elemental diet on clinical symptoms and mucosal immunopathology in type 1 RCD. METHODS: Ten CD patients on a strict gluten-free diet were diagnosed with type 1 RCD after extensive clinical evaluation in a tertiary referral hospital. A 4-week amino-acid-based liquid elemental diet regimen was given with no other treatment, except in 1 patient who also received methotrexate. Duodenal biopsy specimens were obtained before and after treatment for histologic assessment, immunophenotyping of intraepithelial lymphocytes, T-cell receptor clonality, mucosal interleukin (IL)-15 expression, flow-cytometric analysis of interferon (IFN)-gamma-secreting T cells, and whole biopsy specimen IFN-gamma messenger RNA determination. RESULTS: Nine patients completed the treatment; however, 1 patient did not tolerate the diet. Histologic improvement and reduced epithelial IL-15 were seen in 8 patients, whereas IFN-gamma-secreting mucosal T cells and IFN-gamma messenger RNA levels decreased in 4 and 7 patients, respectively. Clinical improvement was noted in 6 patients, with 1 patient showing normalization of hypoalbuminemia. Three patients could discontinue their total parenteral nutrition. CONCLUSIONS: Persistent mucosal IFN-gamma and IL-15 production often occurs in type 1 RCD despite conventional treatment. Elemental diet is a therapeutic option that can provide long-term immunopathologic and clinical improvement of this difficult condition.