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Cells Dec 2021Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of...
Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid-Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario.
Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid-base imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid-base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.
Topics: Antiporters; Chloride-Bicarbonate Antiporters; Humans; Models, Biological; Neuroendocrine Tumors; Polyendocrinopathies, Autoimmune; Stomach Neoplasms; Sulfate Transporters
PubMed: 34944008
DOI: 10.3390/cells10123500 -
World Journal of Gastroenterology Nov 2021Reliable diagnostics are a major challenge for the detection and treatment of () infection. Currently at the forefront are non-invasive urea breath test (UBT) and stool... (Review)
Review
Reliable diagnostics are a major challenge for the detection and treatment of () infection. Currently at the forefront are non-invasive urea breath test (UBT) and stool antigen test (SAT). Polymerase chain reaction (PCR) is not endorsed due to nonspecific primers and the threat of false-positives. The specificity of DNA amplification can be achieved by nested PCR (NPCR), which involves two rounds of PCR. If the primers are properly designed for the variable regions of the 16S rRNA gene, it is not difficult to develop an NPCR assay for the unambiguous identification of . Elaborate NPCR for a 454 bp amplicon was validated on 81 clinical biopsy, stool, and saliva samples, each from the same individuals, and compared with available assays, namely histology, rapid urease test, SAT, and C-UBT. The assay was much more sensitive than simple PCR, and it was equally sensitive in biopsy samples as the C-UBT test, which is considered the gold standard. In addition, it is sufficiently specific because sequencing of the PCR products exclusively confirmed the presence of -specific DNA. However, due to the threshold and lower abundance, the sensitivity was much lower in amplifications from stool or saliva. Reliable detection in saliva also complicates the ability of to survive in the oral cavity aside from and independent of the stomach. The reason for the lower sensitivity in stool is DNA degradation; therefore, a new NPCR assay was developed to obtain a shorter 148 bp 16S rRNA amplicon. The assay was validated on stool samples from 208 gastroenterological patients and compared to SAT results. Surprisingly, this NPCR revealed the presence of in twice the number of samples as SAT, indicating that many patients are misdiagnosed, not treated by antibiotics, and their problems are interpreted as chronic. Thus, it is unclear how to properly diagnose in practice. In the first approach, SAT or UBT is sufficient. If samples are negative, the 148 bp amplicon NPCR assay should be performed. If problems persist, patients should not be considered negative, but due to threshold abundance, they should be periodically tested. The advantage of NPCR over UBT is that it can be used universally, including questionable samples taken from patients with achlorhydria, receiving proton pump inhibitors, antibiotics, bismuth compound, intestinal metaplasia, or gastric ulcer bleeding.
Topics: Breath Tests; DNA; Helicobacter Infections; Helicobacter pylori; Humans; RNA, Ribosomal, 16S; Sensitivity and Specificity; Urea; Urease
PubMed: 34887630
DOI: 10.3748/wjg.v27.i41.7100 -
AACE Clinical Case Reports 2021Calcium is an essential mineral involved in the functioning of nearly every human cell. Calcium levels are regulated by dietary absorption, vitamin D status, and...
OBJECTIVE
Calcium is an essential mineral involved in the functioning of nearly every human cell. Calcium levels are regulated by dietary absorption, vitamin D status, and parathyroid hormone (PTH). This report describes a patient in whom childhood bowel resection and partial gastrectomy resulted in malabsorptive hypocalcemia in adulthood.
CASE REPORT
A 21-year-old man presented with syncope and a fall resulting in a right femoral neck fracture. His medical history included small bowel obstructions at age 9 requiring bowel resection, and at age 12 with gastric perforation and partial gastrectomy. Laboratory values showed calcium level of 4.9 mg/dL (8.9-10.3 mg/dL). PTH level was 273 pg/mL (12.0-88.0 pg/mL), 25-hydroxy-vitamin D was 28 ng/dL (30-100 ng/mL), and 1,25-dihydroxy-vitamin D was 54 pg/dL (18-72 pg/mL). Furthermore, magnesium and phosphorus levels were 2.1 mg/dL (1.5-2.6 mg/dL) and 4.4 mg/dL (2.4-4.7 mg/dL), respectively. Calcium levels improved to 9.5 mg/dL on 10% calcium gluconate drip but could not be maintained above 7 mg/dL on oral calcium carbonate supplementation, despite doses as high as 3750 mg three times daily with calcitriol 0.75 mcg twice daily. After switching from calcium carbonate to calcium citrate 3500 mg three times daily, the calcium level improved and was maintained between 8.3 and 9.0 mg/dL.
DISCUSSION
High calcium needs, other nutrient deficiencies, and response to calcium citrate versus calcium carbonate suggest malabsorption from achlorhydria and small bowel resection.
CONCLUSION
This case emphasizes the gastrointestinal physiology in calcium homeostasis and highlights the recognition of hypocalcemia as a complication of gastric and bowel resection.
PubMed: 34522774
DOI: 10.1016/j.aace.2021.04.002 -
PloS One 2021Hypochlorhydria (gastric pH >4) increases susceptibility to diarrhoea, iron deficiency, and gastric cancer. We sought to clarify the prevalence of this condition and its...
BACKGROUND
Hypochlorhydria (gastric pH >4) increases susceptibility to diarrhoea, iron deficiency, and gastric cancer. We sought to clarify the prevalence of this condition and its predisposing factors in Zambia by pooling data from previous studies conducted in hospital and community settings.
METHODS
Gastric pH was measured in participants from five separate studies by collecting gastric aspirate from fasted adults and children under 3 years of age undergoing gastroscopy. Gastric pH was correlated with serological testing for Human Immunodeficiency Virus (HIV) and Helicobacter pylori (H. pylori) infections.
RESULTS
We studied 597 individuals (487 adults and 110 children). Hypochlorhydria was present in 53% of adults and 31% of children. HIV infection was detected in 41% of adults and 11% of children. H. pylori serology was available for 366 individuals: 93% of adults and 6% of children were seropositive. In univariate analysis, hypochlorhydria was significantly associated with HIV seropositivity (OR 1.7; 95% CI 1.2-2.4; p = 0.004) and H. pylori antibody seropositivity (OR 4.9; 95% CI 2.8-8.6; p<0.0001), and with advancing age in HIV negative individuals (p = 0.0001). In multivariable analysis, only H. pylori was associated with hypochlorhydria (OR 4.0; 95% CI 2.2-7.2; p<0.0001) while excluding possible exposure to proton pump inhibitors.
CONCLUSIONS
Hypochlorhydria is common in our population, with H. pylori being the dominant factor. Only young HIV seronegative individuals had a low prevalence of hypochlorhydria. This may have implications for the risk of other health conditions including gastric cancer.
Topics: Achlorhydria; Adult; Aged; Child; Child, Preschool; Endoscopy; Female; Gastroscopy; HIV; HIV Infections; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Infant; Male; Middle Aged; Risk Factors; Stomach; Stomach Neoplasms
PubMed: 34449790
DOI: 10.1371/journal.pone.0256487 -
Journal of Medical Cases May 2021Chronic diarrhea is a common chief complaint in the pediatric population with a wide range of diagnostic differentials; as such, whilst suspecting common causes, less...
Chronic diarrhea is a common chief complaint in the pediatric population with a wide range of diagnostic differentials; as such, whilst suspecting common causes, less prevalent conditions tend to be overlooked, such as neuroendocrine tumor pathologies. VIPomas are characterized by hypersecretion of the vasoactive intestinal peptide (VIP), causing watery diarrhea, hypokalemia, and achlorhydria. Nonetheless, its low incidence rate in children makes it an easily unnoticed pathology. Herein, we report a case of a 14-year-old female patient and a review of relevant literature. The patient complained of 7-month history of watery diarrhea, multiple emetic episodes, and relevant past medical history of multiple hospitalizations. Chronic diarrheal disease work-up studies, including a high VIP scintigram, showed a lesion suggestive of a VIPoma-type neuroendocrine pancreatic tumor. A distal pancreatectomy was performed with a complete resolution of the symptoms. When faced with a pediatric patient presenting with chronic secretory diarrhea and whose work-up studies rule out the most common pathologies, the possible presence of a neuroendocrine tumor as VIPoma should be considered.
PubMed: 34434457
DOI: 10.14740/jmc3535 -
Molecular Pharmaceutics Sep 2021Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. drug dissolution depends on the GI...
Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. and Bermejo, M. ). The dissolution of an ionizable drug may benefit from manipulating variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (, proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds' dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties ( solubility and p) and its interplay with the pH modifier p or ps. As an example of this complex interaction, for basic drugs with high p and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as p, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to multi-compartment dissolution vessels and are validated by experiments in the gastrointestinal simulator. This model's predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both and conditions.
Topics: Administration, Oral; Betaine; Biological Availability; Chemistry, Pharmaceutical; Computer Simulation; Drug Design; Drug Liberation; Excipients; Fumarates; Gastrointestinal Absorption; Humans; Hydrogen-Ion Concentration; Models, Biological; Solubility; Tartrates
PubMed: 34428047
DOI: 10.1021/acs.molpharmaceut.1c00262 -
Case Reports in Hematology 2021Vitamin B12 is an essential nutrient which plays an important role in neurological function, hematopoiesis, and DNA synthesis. Low levels usually stem from either poor...
Vitamin B12 is an essential nutrient which plays an important role in neurological function, hematopoiesis, and DNA synthesis. Low levels usually stem from either poor intake or a malabsorptive process. Presently, the most common cause of vitamin B12 deficiency is food-bound cobalamin malabsorption, which occurs when there is impaired release of vitamin B12 from ingested food due to an outstanding factor preventing the release of the nutrient from its transport protein. Such causes include achlorhydria, gastritis, gastrectomy, or the use of PPIs or antacids. A rarer cause is autoimmune chronic atrophic gastritis, resulting in pernicious anemia. In this disease process, there is destruction of parietal cells and thus a reduction in intrinsic factor, which is essential to the absorption of vitamin B12. Deficiency will result in a variety of abnormalities including but not limited to pancytopenia, paresthesias, and neuropsychiatric symptoms. A rare manifestation of vitamin B12 deficiency is hemolytic anemia, which occurs due to intramedullary and extramedullary dysfunction. This case describes a 46-year-old male with no past medical history who presented with chest pain, fatigue, and progressive weakness, found to have hemolytic anemia, ultimately attributed to vitamin B12 deficiency. Antiparietal cell antibodies and intrinsic factor antibodies (IFA) were both negative. Still, the patient underwent an endoscopy with biopsies of the stomach; pathology was consistent with chronic metaplastic atrophic gastritis. The patient improved with intramuscular vitamin B12 supplementation. This case highlights both a rare cause and presentation of vitamin B12 deficiency. Patients with autoimmune chronic atrophic gastritis should have antiparietal cell or intrinsic factor antibodies. Still, seronegative patients have been reported, like this patient. Additionally, hemolytic anemia secondary to vitamin B12 deficiency is uncommon. The presentation will usually mirror that of a thrombotic microangiopathy (TMA), including hemolytic anemia with schistocytes on peripheral blood smear and thrombocytopenia, as it did in this patient. This clinical entity is described as pseudothrombotic microangiopathy and is crucial to identify in order to prevent the initiation of invasive treatment strategies such as plasmapheresis.
PubMed: 34373795
DOI: 10.1155/2021/9571072 -
Archives of Pathology & Laboratory... Mar 2022Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of...
CONTEXT.—
Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known, and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports.
OBJECTIVE.—
To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization.
DESIGN.—
This is a retrospective clinicopathologic study of GNETs in the body/fundus during a period of 15 years (2005-2019).
RESULTS.—
Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal and of higher grade (P = .03) than "true" sporadic GNETs.
CONCLUSIONS.—
A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use.
Topics: Animals; Enterochromaffin-like Cells; Humans; Hyperplasia; Neuroendocrine Tumors; Proton Pump Inhibitors; Retrospective Studies; Stomach Neoplasms
PubMed: 34283890
DOI: 10.5858/arpa.2020-0315-OA -
The American Journal of Clinical... Oct 2021Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The...
BACKGROUND
Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The crystalline vitamin B-12 form, found in fortified foods, does not require gastric acid for its absorption and could thus be beneficial for older adults with hypochlorhydria, but evidence is lacking.
OBJECTIVES
To investigate associations of AG and PPI use with vitamin B-12 status, and the potential protective role of fortified foods, in older adults.
METHODS
Eligible participants (n = 3299) not using vitamin B-12 supplements were drawn from the Trinity-Ulster and Department of Agriculture cohort, a study of noninstitutionalized adults aged ≥60 y and recruited in 2008-2012. Vitamin B-12 status was measured using 4 biomarkers, and vitamin B-12 deficiency was defined as a combined indicator value < -0.5. A pepsinogen I:II ratio <3 was considered indicative of AG.
RESULTS
AG was identified in 15% of participants and associated with significantly lower serum total vitamin B-12 (P < 0.001) and plasma holotranscobalamin (holoTC; P < 0.001), and higher prevalence of vitamin B-12 deficiency (38%), compared with PPI users (21%) and controls (without AG and nonusers of PPIs; 15%; P < 0.001). PPI drugs were used (≥6 mo) by 37% of participants and were associated with lower holoTC concentrations, but only in participants taking higher doses (≥30 mg/d). Regular, compared with nonregular, consumption of fortified foods (i.e., ≥5 and 0-4 portions/wk, respectively) was associated with higher vitamin B-12 biomarkers in all participants, but inadequate to restore normal vitamin B-12 status in those with AG.
CONCLUSIONS
Older adults who have AG and/or use higher doses of PPIs are more likely to have indicators of vitamin B-12 deficiency. Fortified foods, if consumed regularly, were associated with enhanced vitamin B-12 status, but higher levels of added vitamin B-12 than currently provided could be warranted to optimize status in people with AG.
Topics: Achlorhydria; Aged; Aging; Biomarkers; Female; Food, Fortified; Gastritis, Atrophic; Humans; Male; Nutritional Status; Pepsinogens; Prevalence; Proton Pump Inhibitors; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex
PubMed: 34134144
DOI: 10.1093/ajcn/nqab193 -
Digestive and Liver Disease : Official... Dec 2021In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate.
BACKGROUND
In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate.
AIMS
To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG.
METHODS
A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene.
RESULTS
Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p < 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p < 0.0001). Streptococcaceae were more abundant in cases (p < 0.0001), Prevotellaceae in controls (p < 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer.
CONCLUSION
Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.
Topics: Achlorhydria; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cross-Sectional Studies; Female; Firmicutes; Gastritis, Atrophic; Gastrointestinal Microbiome; Humans; Male; Middle Aged; Precancerous Conditions; Risk Assessment; Stomach Neoplasms
PubMed: 34116969
DOI: 10.1016/j.dld.2021.05.005