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.

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.

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.

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.

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.

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.

Impact of COVID-19 on liver function: results from an internal medicine unit in Northern Italy.

Little is known regarding coronavirus disease 2019 (COVID-19) clinical spectrum in non-Asian populations. We herein describe the impact of COVID-19 on liver function in 100 COVID-19 consecutive patients (median age 70 years, range 25-97; 79 males) who were admitted to our internal medicine unit in March 2020. We retrospectively assessed liver function tests, taking into account demographic characteristics and clinical outcome. A patient was considered as having liver injury when alanine aminotransferase (ALT) was > 50 mU/ml, gamma-glutamyl transpeptidase (GGT) > 50 mU/ml, or total bilirubin > 1.1 mg/dl. Spearman correlation coefficient for laboratory data and bivariable analysis for mortality and/or need for intensive care were assessed. A minority of patients (18.6%) were obese, and most patients were non- or moderate-drinkers (88.5%). Liver function tests were altered in 62.4% of patients, and improved during follow-up. None of the seven patients with known chronic liver disease had liver decompensation. Only one patient developed acute liver failure. In patients with altered liver function tests, PaO2/FiO2 < 200 was associated with greater mortality and need for intensive care (HR 2.34, 95% CI 1.07-5.11, p = 0.033). To conclude, a high prevalence of altered liver function tests was noticed in Italian patients with COVID-19, and this was associated with worse outcomes when developing severe acute respiratory distress syndrome.

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.

Polysorbate 80 add-on therapy in the treatment of Helicobacter pylori infection: Polysorbate 80 and HP antibiotic resistance.

Polysorbate 80, a sorbitan derivate, is a surfactant used as an emulsifier in some foods in concentrations of up to 0.5%. It was recently shown in vitro that polysorbate 80 decreases the minimum bactericidal concentrations of clarithromycin and metronidazole and may also revert antibiotic resistance. We report the case of an adult man, suffering from symptomatic Helicobacter pylori (HP) infection resistant to two courses of treatment with PPI plus amoxicillin and clarithromycin, and PPI plus clarithromycin and metronidazole. He was treated with a further antibiotic approach consisting of two-week administration of clarithromycin, metronidazole, PPI and polysorbate 80 as an add on therapy. Eradication of infection was confirmed by 13C-urea breath test two and five months after completion of the treatment course. Complete regression of symptoms was also achieved. To our knowledge, this is the first case of HP infection eradicated with a combination therapy based on polysorbate 80 added to antibiotics.

Natural history of autoimmune atrophic gastritis: a prospective, single centre, long-term experience.

BACKGROUND: Autoimmune atrophic gastritis (AAG) is an immune-mediated disorder characterised by destruction of gastric oxyntic mucosa AIM: To explore gastric histopathological evolution in a cohort of AAG patients over a prolonged follow-up METHODS: Single centre prospective study enrolling consecutive patients with histologically confirmed AAG between 2000 and 2018. All AAG patients undergoing endoscopic follow-up every 1-3 years were classified as having stages 1, 2 or 3 according to atrophy severity (mild, moderate and severe). AAG patients with either glandular or neuroendocrine dysplasia/neoplasia were classified as having stage 4. Disease stage progression, and changes in serum anti-parietal cell antibody (PCA), chromogranin A and gastrin-17 were assessed. RESULTS: In total, 282 AAG patients (mean age 60.3 years; F:M ratio 2.4:1; median follow-up 3 years, interquartile range 1-7) were enrolled. All patients with stages 1 or 2 progressed to stage 2 or 3 over time with a steady trend (P = .243) and regression from a severe to a milder stage was never noticed. Disease progression of patients with stages 1 or 2 occurred within the first 3 years. PCA positivity rate did not change over time. Stage 3 patients had higher gastrin-17 levels compared to patients with stages 1 and 2 (median 606 vs 295 pg/mL; P < .001). In stage 3, the hazard ratio for the risk of developing stage 4 was 6.6 (95% CI 1.5-29; P = .001). CONCLUSIONS: AAG is a steadily progressive disease, in which stages 1 and 2 always progress to stage 3. The risk of developing a complicated disease stage is greater in patients with more severe gastric lesions.

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.

Determinants of diagnostic delay in autoimmune atrophic gastritis.

BACKGROUND: Autoimmune atrophic gastritis (AAG) is characterised by a wide clinical spectrum that could delay its diagnosis. AIMS: To quantify the diagnostic delay in patients suffering from AAG and to explore possible risk factors for longer diagnostic delay. METHODS: Consecutive patients with AAG evaluated at our gastroenterological outpatient clinic between 2009 and 2018 were included. Diagnostic delay was estimated as the time lapse occurring between the appearance of the first likely symptoms, laboratory alterations, and other clues indicative of AAG and the final diagnosis. Patient-dependent and physician-dependent diagnostic delays were also assessed. Multivariable regression models were fitted. RESULTS: 291 patients with AAG (mean age at diagnosis 61 ± 15 years; F:M ratio = 2.3:1) were included. The median overall diagnostic delay was 14 months (interquartile range [IQR] 4-41). Factors associated with longer median overall diagnostic delay were female sex (17 months, IQR 5-48), having a previous misdiagnosis (36 months, IQR 17-125) and a history of infertility/miscarriages (33 months, IQR 8-120), whereas a higher level of education was associated with longer patient-dependent diagnostic delay (4 months, IQR 1-12). First evaluation by a gastroenterologist was associated with a median longer diagnostic delay (6 months, IQR 2-15) compared to an internist (3 months, IQR 3-31) and a haematologist (1 month, IQR 0-2). Age, socioeconomic or marital status did not affect the diagnostic delay. CONCLUSIONS: AAG is burdened by substantial diagnostic delay, especially in female patients, and due to lack of awareness, particularly among gastroenterologists. Uncommon vitamin B12 deficiency-related manifestations are overlooked and may prolong the diagnostic delay.

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.

Non-Celiac Gluten Sensitivity in patients with severe abdominal pain and bloating: The accuracy of ALCAT 5.

BACKGROUND AND AIMS: Non-Celiac Gluten Sensitivity (NCGS) is a recently proposed clinical condition causing both intestinal and extra-intestinal symptoms, without gastrointestinal lesions, which improve on avoiding gluten intake, in the absence of celiac disease and wheat allergy. The prevalence of this condition is still a matter of debate, in part due to the very recent introduction of an accepted diagnostic test, a double-blind, placebo controlled gluten challenge. However, this is a lengthy and cumbersome procedure, theoretically burdened by a significant reduction of patient compliance. ALCAT 5 is an automated in vitro test evaluating the toxic effect of gluten on neutrophils by the exposure of these cells to a gluten-containing extract of gluten-containing cereals. The test is very simple to perform, the results are rapidly obtained, and might represent, if sufficiently accurate, a promising alternative to diagnose gluten intolerance. The aim of this study was the comparison of ALCAT 5 results with those of a double-blind, placebo-controlled, gluten challenge, in a group of patients with clinically-suspected NCGS. METHODS: Twenty-five patients (M/F 3/22, mean age 32 ± 4 yrs) with severe functional abdominal pain and bloating, who had previously undergone the ALCAT 5 test, were enrolled. All the subjects reported their symptoms on a gluten-containing diet and considered gluten the causal agent. Following the Salerno Experts' Criteria, they underwent a double-blind, placebo controlled trial with gluten vs placebo. A mean value during gluten ingestion >30% of the value during placebo was considered as indicative of gluten sensitivity. RESULTS: After blinded administration of gluten, 13 out of 25 (52%) patients showed an increase in the severity of abdominal pain, and 11 out of 25 (44%) showed an increase in the severity of abdominal bloating. Considering these two symptoms together, in 16 patients out of 25 (64%), blinded gluten administration induced an increase of abdominal pain and/or bloating. The ALCAT 5 test proved to be positive in 20 and negative in 5 patients. In sixteen patients out of 25 the result of ALCAT 5 agreed with the double-blind trial (64%). In particular, both tests were positive in 14 patients and negative in 2. CONCLUSIONS: In this subgroup of patients, ALCAT 5 could be used to support the clinical suspicion of the presence of NCGS and to address these patients to a blinded gluten challenge.

The diagnosis of small intestinal bacterial overgrowth: Two steps forward, one step backwards?

Small intestinal bacterial overgrowth (SIBO) was originally described decades ago as a cause of malabsorption among individuals with abnormal intestinal anatomy and/or impaired gastric acid secretion and intestinal motor functions. More recently, the concept of SIBO has been expanded to explain symptoms among a much broader patient population-a move that brings the definition of SIBO into much sharper focus. For largely logistical reasons, breath tests and, especially, those based on the excretion of hydrogen consequent on the fermentation of unabsorbed carbohydrate substrates, have almost entirely replaced jejunal aspirates in the diagnosis of SIBO. Ever bedeviled by concerns regarding their reliability, hydrogen breath tests have now come under even more critical scrutiny with the study from Sundin and colleagues in this issue suggesting that their sole function is to detect carbohydrate malabsorption and that they are incapable of defining SIBO.

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.