Long-Term Natural History of Autoimmune Gastritis: Results From a Prospective Monocentric Series.

INTRODUCTION: The natural history of autoimmune gastritis (AIG) has been poorly described. In this study, we report the long-term natural history and clinical clustering of the full spectrum of AIG, from the potential to the complicated stage. METHODS: Prospective single-center study conducted in a tertiary referral center. Patients with AIG at any stage (0 = potential; 1 = early; 2 = florid; 3 = severe; and 4 = complicated) were enrolled (January 2000-December 2022). The histopathological evolution, the clinical presentation, and the correlates of evolution of potential AIG were assessed. RESULTS: Four hundred ninety-eight patients with AIG (mean age 56.7 ± 15.2 years, F:M ratio 2.5:1) were included, of whom 93 experienced potential AIG. The maximum disease duration was 27 years (median 18, interquartile range 14-23), while the overall median follow-up was 52 months (interquartile range 12-95). Age was significantly lower in stage 0 compared with that in the other stages. Accidental histologic evidence and hematologic findings were the most common clusters of diagnosis. The overall median rate of progression was 7.29 per 100 persons/yr (95% confidence interval [CI] 6.19-8.59), while the stage-specific rates of progression were 10.85 (stage 0; 95% CI 7.75-15.18), 14.83 (stages 1-2; 95% CI 11.89-18.49), and 2.68 (stage 3; 95% CI 1.88-3.84). Newly onset neoplastic complications at follow-up occurred in 41/483 patients (8.5%; 23 neuroendocrine tumors and 18 epithelial dysplasia). No cases of adenocarcinoma were noticed. Male sex was associated with a greater likelihood of evolving from potential AIG to overt AIG. DISCUSSION: AIG is a progressive disorder, with a virtually absent risk of gastric adenocarcinoma. Patients with potential AIG should be monitored because they carry a high risk of evolving into overt AIG.

Impaired Quality of Life in Patients with Autoimmune Atrophic Gastritis.

BACKGROUND: Autoimmune atrophic gastritis (AAG) leads to vitamin B12 deficiency that may manifest with neuropsychiatric disorders, such as emotional instability, cognitive deficits, depression, and personality changes. AIMS: To evaluate the quality of life (QoL) in patients with AAG and the interplay between QoL, psychopathological symptoms, and demographic factors. METHODS: This is an observational, cross-sectional study including 102 patients with AAG (mean age 62 ± 13 years), 100 with functional gastrointestinal disorders (mean age 38.3 ± 17 years), 100 with other chronic organic gastrointestinal diseases (mean age 50.9 ± 21.4 years), and 100 healthy controls (mean age 37.5 ± 18.9 years). The 36-Item Short Form Health Survey questionnaire (SF-36) and the General Health Questionnaire-12 were administered. The results of the scales were compared among the study groups. Linear regression analyses were fitted to identify independent predictors of QoL in AAG patients. RESULTS: QoL was significantly different among the four groups in all subdomains. In particular, the AAG group was significantly (P < 0.01) more impaired than the functional gastrointestinal disorder group in the physical functioning and it was significantly more impaired than the control group in all the quality of life subdomains with exception of vitality. Vitamin B12 serum level was a significant (P < 0.04) independent predictor of physical functioning. CONCLUSIONS: Patients with AAG have a decreased QoL compared to healthy controls, but in line with that of patients with organic gastrointestinal disorders. Physical component is responsible for worsening QoL. Vitamin B12 supplementation may positively affect patient's perception of body functioning.

Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity.

OBJECTIVE: Non-coeliac gluten sensitivity (NCGS) is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods, in the absence of coeliac disease (CD) and wheat allergy. No biomarkers are available to diagnose NCGS and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. The aim of our work was to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm. DESIGN: In a multicentre study, we enrolled 86 patients with either self-reported or double-blind confirmed NCGS, 59 patients with diarrhoea-predominant IBS (IBS-D), 15 patients with CD and 25 asymptomatic controls (AC). Zonulin serum levels were assessed and the associated diagnostic power calculated. Clinical and symptomatic data were recorded. The effect of diet on zonulin levels was evaluated in a subgroup of patients with NCGS. RESULTS: Compared with ACs, the NCGS, irrespective of modality of diagnosis, and patients with CD had significantly increased levels of zonulin, as did both NCGS and patients with CD compared with participants with IBS-D. Self-reported NCGS showed increased zonulin levels compared with double-blind confirmed and not-confirmed NCGS. Six-month wheat avoidance significantly reduced zonulin levels only in HLA-DQ2/8-positive participants with NCGS. The diagnostic accuracy of zonulin levels in distinguishing NCGS from IBS-D was 81%. After exclusion of CD, a diagnostic algorithm combining zonulin levels, symptoms and gender improved the accuracy to 89%. CONCLUSION: Zonulin can be considered a diagnostic biomarker in NCGS and combined with demographic and clinical data differentiates NCGS from IBS-D with high accuracy. Wheat withdrawal was associated with a reduction in zonulin levels only in NCGS carrying HLA genotype.

Prevalence and pathophysiology of post-prandial migraine in patients with functional dyspepsia.

BACKGROUND: Migraine is a condition frequently associated with gastrointestinal disorders. Previous reports have shown the relationship between irritable bowel syndrome and migraine, but no data are yet available in patients with functional dyspepsia. We therefore evaluated whether alteration of gastric sensorimotor activity may be related to migraine. METHODS: Sixty patients affected by functional dyspepsia, 38 with postprandial distress syndrome and 22 with epigastric pain syndrome were enrolled in a cohort study. Presence and severity of dyspeptic symptoms, migraine presence and severity, gastric sensitivity thresholds during fasting and postprandial period, gastric accommodation and gastric emptying time were evaluated. RESULTS: In epigastric pain syndrome, 12/22 (54%) patients suffered from migraine and this condition was never correlated with meal ingestion. In postprandial distress syndrome patients, 29/38 (76%) suffered from migraine, in 26/29 (89%) its onset was considered as meal-related, and migraine severity was significantly correlated with postprandial modification of the gastric discomfort threshold (r = -0.73; p < 0.001). In patients with postprandial distress syndrome, in the subgroup with moderate to severe migraine, the severity of fullness and early satiation was significantly higher than in patients with mild or absent migraine. In patients with moderate to severe migraine, gastric accommodation, sensitivity thresholds and gastric emptying time were similar to patients with mild or no migraine. CONCLUSIONS: In patients with functional dyspepsia and postprandial symptoms, migraine is a very frequent comorbidity. On clinical grounds, it is associated with an increased severity of fullness and early satiation and, on pathophysiological grounds, it seems correlated with postprandial hypersensitivity.

Alterations of Inflammatory and Matrix Production Indices in Celiac Disease With Low Bone Mass on Long-term Gluten-free Diet.

BACKGROUND: A clinically meaningful impairment of bone mass secondary to malabsorption is frequent in untreated celiac disease. In adult patients, a rigorous gluten-free diet (GFD) significantly improves, but does not always normalize, bone mineral density (BMD). The reason for this marginal response is unclear. Accordingly, we evaluated the role of both local and systemic factors for bone loss in celiac patients on long-term GFD. STUDY: In a prospective cohort, 22 patients with low lumbar and/or femoral BMD and 22 with normal BMD underwent bone and mineral metabolism evaluation: we tested calcium, phosphate, parathyroid hormone, and vitamin D; telopeptide of type I collagen, a bone resorption index; propeptide of type I procollagen, a bone neoformation index; receptor antagonist of NF-kB ligand, an osteoclast-stimulating factor; osteoprotegerin (OPG), a decoy receptor for RANKL. Sunlight exposure and physical exercise were measured. RESULTS: Patients with bone loss showed prevalently osteopenia, severe osteoporosis was rare. In comparison with normal BMD patients, they showed higher serum OPG, telopeptide, and lower serum propeptide, suggesting an increased bone turnover. Lumbar T-score was negatively correlated with OPG, telopeptide and RANKL and positively with propeptide. Propeptide was negatively correlated with OPG and telopeptide. OPG was positively correlated with telopeptide. CONCLUSIONS: The persistent activation of inflammation should be considered the main pathophysiological mechanism for bone defect in celiac disease patients with bone loss on long-term GFD. High levels of OPG, an attempt at protective mechanism, and low levels of propeptide of type I procollagen, reflecting an insufficient matrix production, characterize this subgroup of patients.

The Italian Mastocytosis Registry: 6-year experience from a hospital-based registry.

AIM: We collected 'real-life' data on the management of patients with mastocytosis in the Italian Mastocytosis Registry. METHODS: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers. RESULTS: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable. CONCLUSION: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.

Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial.

BACKGROUND & AIMS: There is debate over the existence of nonceliac gluten sensitivity (NCGS) intestinal and extraintestinal symptoms in response to ingestion of gluten-containing foods by people without celiac disease or wheat allergy. We performed a randomized, double-blind, placebo-controlled, cross-over trial to determine the effects of administration of low doses of gluten to subjects with suspected NCGS. METHODS: We enrolled 61 adults without celiac disease or a wheat allergy who believed ingestion of gluten-containing food to be the cause of their intestinal and extraintestinal symptoms. Participants were assigned randomly to groups given either 4.375 g/day gluten or rice starch (placebo) for 1 week, each via gastrosoluble capsules. After a 1-week gluten-free diet, participants crossed over to the other group. The primary outcome was the change in overall (intestinal and extraintestinal) symptoms, determined by established scoring systems, between gluten and placebo intake. A secondary outcome was the change in individual symptom scores between gluten vs placebo. RESULTS: According to the per-protocol analysis of data from the 59 patients who completed the trial, intake of gluten significantly increased overall symptoms compared with placebo (P = .034). Abdominal bloating (P = .040) and pain (P = .047), among the intestinal symptoms, and foggy mind (P = .019), depression (P = .020), and aphthous stomatitis (P = .025), among the extraintestinal symptoms, were significantly more severe when subjects received gluten than placebo. CONCLUSIONS: In a cross-over trial of subjects with suspected NCGS, the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo. Clinical trial no: ISRCTN72857280.

Breath Methane Excretion Is not An Accurate Marker of Colonic Methane Production in Irritable Bowel Syndrome.

OBJECTIVES: The role of colonic methane production in functional bowel disorders is still uncertain. In small samples of irritable bowel syndrome (IBS) patients, it was shown that methane breath excretion correlates with clinical presentation and delayed gastrointestinal transit time. The aim of this study was to evaluate the relationship between intestinal production and breath excretion of CH4 and to correlate CH4 production with the presence and the severity of symptoms, in a large cohort of IBS patients and in a group of healthy volunteers. METHODS: A group of 103 IBS patients and a group of 28 healthy volunteers were enrolled. The presence and severity of symptoms and gastrointestinal transit were evaluated in all subjects, who underwent breath H2/CH4 measurement for 7 h after lactulose to identify breath excretors of these gases; H2 and CH4 were also measured in rectal samples to identify colonic producers. Cumulative H2 and CH4 excretion and production were evaluated by the area under the time-concentration curve calculation (AUC). RESULTS: In IBS patients, CH4 was detected in rectal samples in 48 patients (47%), but only 27 of them (26% of the 103 enrolled patients) excreted this gas with breath. In CH4 producers, the prevalence and severity of symptoms and gastrointestinal transit time were not significantly different with respect to non-producers. IBS subtypes were homogeneously represented in CH4 producers and in non-producers. Healthy volunteers, compared with IBS patients, showed a significantly lower prevalence of CH4 excretion, whereas no difference was found in the prevalence of colonic CH4 production; moreover, in healthy volunteers compared with IBS, CH4 breath excretion and CH4 production were not different in quantitative terms. CONCLUSION: Our data show that colonic CH4 production is not associated with clinical presentation in IBS patients and does not correlate with symptom severity or with gastrointestinal transit time. Clinical inferences based on breath CH4 excretion should undergo an in-depth revision, as this method is not a good marker of CH4 colonic production.

A laboratory score in the diagnosis of autoimmune atrophic gastritis: a prospective study.

BACKGROUND: Several biomarkers have been proposed for the diagnosis of autoimmune atrophic gastritis (AAG), but at the present there is no appropriate testing strategy for the disease. GOALS: The aim of this study was to develop and validate a laboratory score able to address the diagnosis of AAG in a general practice setting. STUDY: We prospectively evaluated a number of serum biomarkers (vitamin B12, mean corpuscular volume, hemoglobin, gastrin, and chromogranin A levels) in a case-control population and built 2 biochemical scores, the first with all the parameters [Global Score (GS)], and the second as the best statistical combination of them [Simple Score (SS)]. In the second phase we validated the score that proved to be more efficient on a random population referred to our center (Gastroenterology Outpatient Clinic). RESULTS: Both models turned out to be reliable in detecting patients with suspected AAG, showing excellent accuracy [area under the receiver operating curve (AUC-ROC) 0.94; 95% confidence interval (CI), 0.91-0.97 for GS and AUC-ROC 0.93; 95% CI, 0.89-0.86 for SS]. The SS proved to be more convenient because of its accessibility and availability in a general setting and its low cost. The validation of the SS showed a sensitivity of 85.7% (95% CI, 57.2-98.2) and a specificity of 83.7% (95% CI, 74.2-90.89). CONCLUSIONS: Herein, we describe 2 nonexpensive and reliable score models, particularly the SS, that can be applied in daily medical practice for identifying patients potentially affected by AAG.

Fasting and postprandial gastric sensorimotor activity in functional dyspepsia: postprandial distress vs. epigastric pain syndrome.

OBJECTIVES: Little information is available on the mechanisms responsible for dyspeptic symptoms in postprandial distress syndrome (PDS), characterized by the presence of prevalently meal-related early satiation and fullness, and the epigastric pain syndrome (EPS), characterized by the prominent symptom of epigastric pain, generally not meal related. In a group of PDS patients, the presence of hypersensitivity to gastric distension in both fasting and postprandial phases was described as the main pathophysiological mechanism; on the contrary, we have no information on the pathophysiology of EPS. METHODS: Sixty Helicobacter pylori (HP)-negative, irritable bowel syndrome (IBS)-negative, and gastroesophageal reflux disease (GERD)-negative patients with functional dyspepsia according to Rome III criteria underwent symptom, anxiety, depression, and somatization evaluation, gastric barostat test, and gastric emptying time evaluation for solids. Fifteen age- and sex-matched healthy volunteers (HVs) were also enrolled as a control group. RESULTS: In PDS patients, the prevalence of both fasting and postprandial hypersensitivity was higher than in EPS patients, and the extent of postprandial reduction of discomfort threshold was significantly correlated with symptom severity. In EPS patients, gastric volume at fasting discomfort threshold and fasting compliance were significantly lower than in PDS patients. Gastric emptying time and gastric accommodation were similar between the two dyspeptic groups. Dyspeptic patients showed a higher prevalence of psychiatric disorders than HVs, but the prevalence was similar between PDS and EPS patients. CONCLUSIONS: Fasting and postprandial hypersensitivity characterize PDS patients and a reduction of gastric compliance is present in EPS patients. However, the pathophysiology of EPS appears more complex than PDS and further studies are needed to analyze central processing and integration of afferent pathways in order to clarify the role of the central nervous system in this condition.

Infections and gender: clues for diagnosis of adrenal insufficiency-a case report and a review of the literature.

The clinical presentation of adrenal insufficiency, a condition causing adrenal hormone deficiency, is characterised by non-specific symptoms and signs: consequently, an important diagnostic delay is often evident which correlates with an increased mortality. This case report shows how the clustering of some symptoms and signs may hamper the diagnostic suspicion for this condition: serum electrolyte alterations and weight loss, when associated to recurrent infections and, in female patients, an empty sella may further guide the clinician towards a diagnosis of adrenal insufficiency. Accordingly, a clinical approach taking into account gender medicine could improve the diagnostic workup.

The Effect of a Gluten-Free Diet on Vitamin D Metabolism in Celiac Disease: The State of the Art.

Celiac disease is a chronic autoimmune disorder involving the small intestine, characterized by villous atrophy, crypt hyperplasia and an increase in intraepithelial lymphocytes. Due to both calcium malabsorption and immune activation, a high prevalence of bone mass derangement is evident in this condition, regardless of the presence of overt malabsorption. Alterations of mineral metabolism are also frequently described, and in this review, the modifications of serum levels of vitamin D are analyzed, according to the available literature on this topic. In untreated patients, secondary hyperparathyroidism is responsible for the hyperconversion of 25-vitamin D into 1,25-vitamin D making mandatory the determination of serum levels of both vitamin metabolites to avoid a wrong diagnosis of vitamin D deficit. A gluten-free diet allows for a normalization of bone and mineral metabolism, reverting these abnormalities and raising some doubts on the need for vitamin supplementation in all the patients. Data available do not support this wide indication, and a complete evaluation of bone and mineral metabolism should be performed to select patients who need this therapeutic approach.

Common features of patients with autoimmune atrophic gastritis.

BACKGROUND & AIMS: Autoimmune atrophic gastritis (AIG) is characterized by immune-mediated chronic inflammation of the gastric body and fundus, leading to hypo-achlorhydria and vitamin B12 deficiency. We analyzed the clinical features of AIG and sought to identify factors that might be used in diagnosis. METHODS: We collected and analyzed clinical data from 99 consecutive patients (age, 59 ± 17 y) who were diagnosed with AIG, based on histologic factors and the presence of autoantibodies against gastric parietal cells. RESULTS: Clinical factors that led to a diagnosis of AIG included hematologic findings related to vitamin B12 deficiency (n = 37), incidental histologic evidence in gastric biopsy specimens (n = 34), immune disorders (n = 18; 9 were celiac disease), neurologic symptoms (n = 6), and a family history of AIG (n = 4). CONCLUSIONS: Based on an analysis of 99 consecutive patients with AIG, this disorder is not solely a condition of the elderly. Other features to look for in making a diagnosis of AIG include vitamin B12 deficiency, histologic factors, and immune disorders.

Clinical presentation vs endoscopy for an early diagnosis of eosinophilic esophagitis: a case report.

Eosinophilic esophagitis (EoE) is a type-2 mediated, chronic inflammatory disease showing an increase of both incidence and prevalence. Early diagnosis is mandatory, to prevent fibrostenotic complication of the disease. Due to the low sensitivity of the classic endoscopic features of the disease, a strong clinical suspicion should drive the decision to collect mucosal biopsies of the esophagus. We describe the case of an atopic patient suffering from dysphagia with normal esophageal mucosa and frank histological hallmarks of the disease.

The Perception of Lactose-Related Symptoms of Patients with Lactose Malabsorption.

Background: Dairy products are frequently considered responsible for post-prandial symptoms and are withdrawn from the diet, even against medical advice. We analysed the symptoms patients consider as lactose related; we also evaluated if psychological profile may affect the interpretation of the relationship between lactose and symptoms. Methods: In 268 patients undergoing lactose breath test, symptoms considered evoked by lactose intake were recorded and their severity measured. In the second part, symptom onset of 40 randomly selected patients was detected after both lactose and glucose breath test were blindly performed. Questionnaires evaluating anxiety, suggestibility and personality trait were administered. Key Results: Symptoms depending on functional gastrointestinal disorders or reflux disease were frequent in self-reported lactose-intolerant patients. In comparison with lactose malabsorption, these symptoms proved to be more frequent in patients with negative lactose breath test. The blinded administration of lactose and glucose demonstrated that a correct link between lactose intake and symptom onset was possible, only in 47.5% of the subjects, making this test inaccurate. None of the investigated psychological characteristics were different between patients with a nocebo response and patients not experiencing nocebo. Conclusions: Patients with self-reported lactose intolerance are frequently unaware about clinical presentation of this condition, and correct information is needed. The detection of symptom onset after lactose is an inaccurate test for lactose intolerance. Furthermore, the analysis of psychological characteristics of patients undergoing hydrogen breath test is not useful to select the subgroup at risk for a nocebo response. New strategies to diagnose lactose intolerance are mandatory.

Increase of Deep Intraepithelial Lymphocytes in the Oxyntic Mucosa of Patients With Potential and Overt Autoimmune Gastritis.

Pathological correlates of potential autoimmune gastritis (AIG), defined by anti-parietal cell antibody (PCA) positivity in the absence of gastric atrophy, have never been described. We herein aimed to assess intraepithelial lymphocyte (IEL) infiltration in gastric corpus of AIG patients. From 2000 to 2021, among 53 potential AIG patients, we focused on nine (median age 61 years, IQR 53-82; four females) who subsequently developed overt AIG. IEL infiltration of the oxyntic mucosa was assessed before and after developing overt AIG by measuring deep and superficial CD3+ IEL. AIG patients with different degrees of corpus atrophy, healthy controls (HC), active H. pylori gastritis, celiac disease (CD), and Hashimoto's thyroiditis patients were included as controls. Of note, deep, but not superficial, CD3+ IEL count was higher (p<0.001) in potential AIG compared to HC and H. pylori gastritis. Deep CD3+ IEL infiltration did not change before or after the evolution into atrophy (median 9.6, IQR 8.8-12.4, vs 11.3, IQR 9.4-12.9). No difference was found in deep CD3+ IEL infiltration among potential, mild, and severe AIG, and compared to Hashimoto's thyroiditis or CD. A deep CD3+ IEL cut-off of >7/100 epithelial cells allowed discrimination of any AIG stage and severity (AUC=0.842). We conclude that an increased deep CD3+ IEL infiltration of the oxyntic mucosa could represent a marker of potential AIG. Prospective studies including a larger number of potential AIG patients are needed.

Live prey enrichment, with particular emphasis on HUFAs, as limiting factor in false percula clownfish (Amphiprion ocellaris, Pomacentridae) larval development and metamorphosis: molecular and biochemical implications.

In fast growing organisms, like fish larvae, fatty acids provided through live prey are essential to satisfy high energy demand and are required to promote growth. Therefore, in recent decades, a great amount of research has been directed towards the development of lipid enrichment in order to improve larval fish survival and growth. However, in fish, the biochemical and molecular processes related to highly unsaturated fatty acid (HUFA) administration are still poorly understood. In the current study, the false percula clownfish, a short larval phase marine species, was used as an experimental model and the effects of a standard and a HUFAs-enriched diet were tested through a molecular, biochemical, ultrastructural and morphometric approach. Our results support the hypothesis that HUFA administration may improve larval development through the presence of better structured mitochondria, a higher synthesis of energy compounds and coenzymes with a central position in the metabolism, with respect to controls. This higher energy status was confirmed by better growth performance and a shorter larval phase in larvae fed with an enriched diet with respect to the control. This strategy of rapid growth and early energy storage may be considered positively adaptive and beneficial to the survival of this species.