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Gastric carcinoid is a rare type of gastric malignancy accounting for around 7% of all gastrointestinal neuroendocrine tumours (NETs). While most gastric NETs (gNETs) are readily visible through direct visualisation by upper endoscopy, around 25% of gastric carcinoids are invisible because they are located in the submucosal gastric regions of the body and fundus. gNETs located in the intra-mucosal areas can be identified by gastric mapping; this can be done by taking random gastric biopsies from the antrum, body and fundus. We report a case of a well-differentiated gastric NET type 1 with atrophic gastritis diagnosed on upper endoscopy and pathological immunohistochemistry staining. LEARNING POINTS: The case highlights that not all gNETs are visible under direct endoscopic visualisation.It is essential to understand the different types of gNETs.Understand that both type and size of gNETs impact therapeutic implications and prognosis.

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INTRODUCTION: Vitamin B12 deficiency is primarily associated with pernicious anaemia, polyneuropathy, and spinal-cord disease, but publications on its association with hallucinations are on the rise. METHODS: I carried out a systematic literature search on these hallucinations in PubMed, PsycINFO, and Google Scholar, up until July 1, 2023. RESULTS: The search yielded 50 case studies published between 1960 and 2023. The hallucinations described therein are predominantly visual and/or auditory in nature, with 20% being specified as complex, compound, or panoramic. They are often described in the context of vitamin B12-related neuropsychiatric conditions such as dementia, delirium, epilepsy, psychotic disorder, schizoaffective disorder, bipolar disorder, depressive disorder, catatonia, or obsessive-compulsive disorder. In the context of such disorders, they tend to appear first and also often appear to be the first to disappear with cobalamin treatment. Within an average of 2 months, full amelioration was thus obtained in 75% of the cases and partial amelioration in the remaining 25%. Remarkably, a quarter of the cases involved therapy-resistant hallucinations that fully resolved under cobalamin monotherapy, while other neuropsychiatric manifestations of vitamin B12 deficiency disappeared in 60% of the treated cases. Only 32% of the cases involved comorbid pernicious anaemia. This suggests that two separate or diverging pathways exist for perceptual and haematological symptoms of vitamin B12 deficiency. CONCLUSION: In the light of the high prevalence rate of vitamin B12 deficiency in the general population, the findings here presented should be interpreted with great caution. Nonetheless, they offer cues for further research and experimental application in clinical practice. This may be especially relevant in light of the recent increase in the popularity of vegetarianism and the recreational use of nitrous oxide (laughing gas), which are both risk factors for vitamin B12 deficiency.

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Hyperpigmentation is a recognized sign of vitamin B12 deficiency that resolves after vitamin repletion. We present the case of a 58-year-old female with neuropsychiatric symptoms who developed progressive darkening of her hands and feet. A diagnosis of vitamin B12 deficiency secondary to pernicious anemia was made and her symptoms and hyperpigmentation resolved following vitamin repletion. Clinicians should consider vitamin B12 deficiency in the differential diagnosis of palmoplantar hyperpigmentation, as early treatment can avert permanent disability in these patients.

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BACKGROUND/AIM: We aimed to assess gastrointestinal cancers risks in a large cohort of individuals with primary antibody deficiency (PAD) and their association with risk of autoimmune and inflammatory gastrointestinal diseases. METHODS: Investigating a French national database of inpatient admissions between 2010 and 2018, we identified 12,748 patients with PAD and 38,244 control non-exposed individuals. We performed multiple exposed-non-exposed studies using conditional logistic regression. RESULTS: In comparison with non-exposed patients, PAD patients had increased risk of in situ gastric carcinoma (Odds Ratio (OR) =10.5 [95 % CI 2.2; 50.5]), malignant gastric tumor (OR=3.2 [95 % CI 2.2; 4.4]) and colorectal cancer (OR=1.2 [95 % CI 1; 1.5]). PAD patients had also increased risk of pernicious anaemia (OR=8 |95 % CI 5.6; 11.5]), Crohn's disease (OR= 4.4 [95 % CI 3.5; 5.6]), ulcerative colitis (OR=2.9 [95 % CI 2.4; 3.6]) and coeliac disease (OR=13.3 [95 % CI 9.1; 19.5]). Within patients with gastric cancer, those with PAD had increased risk of pernicious anaemia (OR=8.4 [95 % CI 1.5; 215]; p = 0.01) but not of H. pylori infection. CONCLUSIONS: Risk of gastric cancer is particularly high in PAD patients and notably risk of in situ gastric carcinoma in association with pernicious anaemia. It supports indication of early endoscopic screening in these patients.

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BACKGROUND: Pseudo-thrombotic microangiopathy (pseudo- thrombotic microangiopathy (TMA)) is a rare presentation of B12 deficiency. Overlapping features like elevated LDH/total bilirubin with low haemoglobin/haptoglobin/platelets could deceivingly suggest thrombotic thrombocytopenic purpura (TTP) resulting in avoidable procedures/treatments. CASE PRESENTATION: A 36-year-old female with hypothyroidism initially presented to clinic with fatigue, palpitations, lightheadedness, and dyspnoea over a 3-month duration and was found to have a haemoglobin of 5.7 g/dL. She received two packed red blood cell units in the emergency room and subsequently discharged with outpatient follow-up and empiric oral iron. During her follow-up visit, she was found to have easy bruisability, gum bleeding, and generalized weakness from hemolytic anaemia (mean corpuscular volume (MCV) 90 fL, haptoglobin <8 mg/dL, LDH >4,000 U/L and schistocytosis on CBC) and thrombocytopenia of 52 K/uL. Due to PLASMIC score of 6 and suspicion for TTP, she was transferred to our facility and tr eated with three cycles of plasma exchange and prednisone but were discontinued when ADAMTS13 levels returned normal. While the patient had normal B12 levels, further testing revealed positive intrinsic factor antibodies (IF-Ab) and an elevated MMA level of 1.56 umol/L. Replacement with cobalamin led to normalization of labs and symptoms. CONCLUSIONS: Timely diagnosis of pseudo-TMA was exceptionally challenging due to several overlapping features with TTP including normal B12 and normal MCV. B12 levels may falsely appear normal in pernicious anemia due to IF-Ab interference with chemiluminescent immunoassay. Schistocytes lower the MCV in automated cell counters. Lower reticulocyte index (<2%), presence of immature/large platelets and teardrop cells, elevated MMA and a higher LDH (>2500) are indicative of B12 deficiency.

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BACKGROUND: Autoimmune atrophic gastritis (AAG) is rarely associated with coeliac disease (CD). AIMS: To assess the frequency of AAG-CD association and to compare clinical, biochemical, and histological features of adults affected by both diseases (cases) with AAG controls. METHODS: This case-control study included 9 cases (F55%, median age 47, range 23-59yrs) matched (1:3) by age (±4 yrs) and gender to 27 controls randomly selected from our AAG cohort (2009-2021). The AAG and CD diagnosis was based on internationally agreed criteria. RESULTS: Of 434 AAG patients (median age:62.5yrs, range18-92yrs, F:M ratio=2.2:1),9 had a concomitant diagnosis of CD. The occurrence of AAG-CD association was 2% and 1.65% among AAG/CD cohorts, respectively. Cases were significantly younger than AAG cohort (n = 425, p = 0.002). In 4/9cases, AAG was diagnosed by proactive screening for autoimmune disorders. Autoimmune thyroid disorders were present in 5/9 cases. Cases had a significant higher prevalence of normocytic anaemia than controls (p = 0.004). No significant differences were found between cases and controls concerning clinical and histological features. CONCLUSIONS: AAG-CD association is rare. Gastric and duodenal biopsies might be advisable in young people with normocytic anaemia and associated autoimmune disorders to timely diagnose clinically silent conditions.

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Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20-0.50) and pernicious anaemia (0.29, 0.19-0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated.

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Introduction: Pernicious Anaemia is a rare autoimmune disorder prevalent among 0.1% of the general population and is characterised by decreased cobalamin absorption. This condition is overlooked because of its rarity, insidious onset of non-specific symptoms and clinically asymptomatic state. Elevated serum intrinsic factor antibody level along with reduced Vitamin B12 level confirms the diagnosis. Case presentation: Pallor and abdominal tenderness was present. Haematological investigations showed elevated platelet count, elevated Mean Cell Volume reduced haemoglobin level(11.4 g/dl), reduced Vitamin B12 and high serum intrinsic factor antibody level. Serum parietal cell antibody was positive. The patient responded well to parenteral Vitamin B12. Discussion: In Pernicious anaemia, serum intrinsic factor antibody and parietal cell antibody are high which are responsible for reduced Vitamin B12 absorption. Studies have also shown positive correlation between H pylori and Pernicious Anaemia. Neurological symptoms are less common but may present as paraesthesia, changes in gait or spasticity due to peripheral neuropathy. It is also associated with autoimmune diseases. Untreated pernicious anaemia can lead to neurological and gastrointestinal complications. Conclusion: Pernicious Anaemia is an overlooked condition because of its insidious onset of non-specific symptoms, clinically asymptomatic state, rarity and therefore timely diagnosis of Pernicious Anaemia still remains a challenge.

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The association between malignancies and autoimmunity had been well-established. The proposed pathophysiology and causality can be bidirectional. For example, a paraneoplastic syndrome can be triggered by an underlying malignancy or vice versa, where chronic inflammation of organs affected by autoimmunity can induce malignant transformation such as the case with inflammatory bowel disease and colorectal cancer or primary sclerosing cholangitis and hepatobiliary cancer. This report presents a case of autoimmune phenomena, namely, autoimmune hemolytic anemia, pernicious anemia, and Graves disease associated with newly diagnosed breast cancer. We also highlight the postulated pathophysiologic mechanisms in an attempt to answer the question of whether the occurrence of these autoimmune phenomena in our patient is a result of the law of parsimony (Occam's razor), where clinical variables are pathogenically related, or the counterargument, where random events and diseases can take place simultaneously (Hickam's dictum).

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Macrocytosis is defined as a mean corpuscular volume greater than 100 femtolitres (fL). There are several causes for macrocytic anaemia, and they can be divided into megaloblastic or non-megaloblastic anaemia. Vitamin B12 deficiency is one of the most common causes of megaloblastic anaemia. The cause of vitamin B12 deficiency must be evaluated including the presence of pernicious anaemia as it could alter the treatment and follow-up. Pernicious anaemia can be associated with other autoimmune diseases constituting polyglandular syndromes.

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Not required for Clinical Vignette.

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BACKGROUND: Patient and public involvement and engagement (PPIE) is recognized as important for improved quality in health service provision and research. Vitamin B12 deficiency is one area where PPIE has potential to benefit patients, as patients often report sub-optimal care due to diagnostic delay, insufficient treatment and poor relationships with health professionals. OBJECTIVE: In an effort to engage an understudied patient population in health-care quality and safety discussions, and provide patients with an opportunity to have a voice, contribute to research priorities and express their current quality and safety concerns, we hosted a PPIE workshop. METHODS: One researcher (with lived experience) facilitated a one day workshop with 12 patients with varied demographics. The workshop had four components (a) one-to-one sessions with an artist, (b) quality and safety research/education priority setting, (c) comments on research proposals, and (d) development of a PPIE group for future research. RESULTS: All elements of the workshop elicited a number of quality and safety priorities for the group. Priority setting highlighted issues with interpretation of test results, symptom-based treatment, self-medication and relationship with primary care health-care professionals. One of the major safety issues highlighted in the visual art element was feeling ignored, silenced or not listened too by health-care professionals. DISCUSSION: Visual art methods to express experiences of health, and research priority setting tasks achieved the aim of providing patients with an opportunity to have a voice and express concerns about health-care quality and safety issues. The addition of visual art allowed patients to articulate emotions and impacts on everyday life associated with quality and safety. PATIENT OR PUBLIC CONTRIBUTION: A public contributor was involved in preparation of this manuscript. The event aimed to enable PPIE contribution in future research.

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AIMS: Proton pump inhibitors (PPIs) are among the most widely used medications in the United States. Most PPI users have persistent hypergastrinaemia during treatment. However, gastric neuroendocrine tumours diagnosed in long-term PPI users are rarely reported. Their clinicopathological features and prognosis are not characterised. It remains unclear whether or not they can be classified as Type III sporadic tumours. METHODS AND RESULTS: We retrospectively characterised 66 gastric neuroendocrine tumours from patients without atrophic gastritis and gastrinoma from two tertiary care medical centres, including 38 tumours in patients who had used PPIs for at least 1 year and 28 tumours from patients without long-term PPI use (control group, Type III tumours). Compared to controls, tumours from long-term PPI users tended to be in the pT1-2 category (98% versus 79%, P = 0.09) and less often invaded the serosa (3% versus 18%, P = 0.08) or lymphovascular spaces (11% versus 32%, P = 0.06). Using Kaplan-Meier analysis, long-term PPI users had significantly longer overall survival than controls (P = 0.035). While three control patients developed distant metastasis and seven died, long-term PPI users were without distant metastasis (P = 0.06) or death (P = 0.002) during follow-up. However, five long-term PPI users developed additional gastric neuroendocrine tumour(s), while none of the controls did (P = 0.07). CONCLUSIONS: Our results show that gastric neuroendocrine tumours of long-term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long-term PPI users as a separate subtype.

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Vitamin B12 deficiency can be caused by a diverse group of aetiologies. One of the less common of these is an autoimmune condition pernicious anaemia, so named after the most common physiological manifestation of B12 deficiency: anaemia. However, B12 is also necessary for nervous system function and its depletion can lead to dysfunction of the posterior columns of the spinal cord resulting in subacute combined degeneration (SCD). This disease, while debilitating in its acute phase, can usually be mostly if not fully reversed if caught early and treated appropriately. Early detection can prove challenging if there are no haematological manifestations of B12 deficiency and the only guidance is the high index of suspicion. We present a case of pernicious anaemia leading to SCD without any clinical or laboratory findings of anaemia in this report.

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BACKGROUND: Autoimmune atrophic gastritis (AAG) leads to iron and/or vitamin B12 malabsorption, with subsequent haematological alterations which could represent the sole clinical manifestation. We aimed to assess patterns of anaemia and micronutrient deficiencies in patients with AAG at the time of diagnosis. METHODS: Observational, multicentre, cross-sectional study including consecutive adult patients diagnosed with AAG within the last ten years. Cell blood count, red cell distribution width, serum vitamin B12, and ferritin were collected. Multivariate analysis for predictive factors of anaemia was computed. RESULTS: 654 AAG patients (mean age 59.2 ± 13.8 years, female (F): male (M) ratio = 2.3:1) were included. Anaemia was present in 316 patients (48.3%; mean age 60.1 ± 15.8 years, F:M ratio = 2.3:1). Pernicious anaemia (132/316 cases, 41.7%) was more common in males (27.1% versus 12.4%; p = 0.001) and in older patients (63.0 ± 14.6 versus 58.9 ± 14.9 years; p = 0.014), while iron deficiency anaemia (112/316 cases, 35.4%) was more common in females (16.9% versus 10.0%; p = 0.039) and in younger patients (56.8 ± 16.6 versus 60.2 ± 14.6 years; p = 0.043). The prevalence of iron deficiency was equally distributed between anaemic and non-anaemic patients (p = 0.9). Anisocytosis (odds ratio: 10.65, 95% confidence interval: 6.13-18.50, p < 0.0001) was independently associated with anaemia. CONCLUSIONS: Anaemia is a common manifestation in AAG patients, mostly due to micronutrient deficiencies. Scant haematologic alterations and micronutrient deficiencies may precede overt anaemia.

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A 49-year-old female patient presented to our hospital with asthenia, odynophagia, low grade fever, worsening symptoms of chronic depression, and symmetric leg paresthesias. Investigations showed macrocytic anaemia, leucopenia, thrombocytopenia, high lactate dehydrogenase levels and a normal Coombs test. Trilineage dysplasia was detected in the bone marrow biopsy specimen. The diagnostic work-up led us to the diagnosis of pernicious anaemia with a spuriously normal value of vitamin B12 and high titres of anti-intrinsic factor autoantibodies. This case highlights the importance of considering vitamin B12 deficiency in the differential diagnosis of myelodysplasia, even when vitamin B12 levels seem to be normal. LEARNING POINTS: Vitamin B12 deficiency is characterized by neuropsychiatric manifestations and bone marrow failure with accompanying dysplastic changes.Spuriously normal vitamin B12 levels can occur in pernicious anaemia due to anti-intrinsic factor autoantibody interference in the laboratory assay.Myelodysplastic syndromes and vitamin B12 deficiency share clinical and laboratory similarities, so a correct differential diagnosis is crucial for adequate treatment.

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INTRODUCTION: The aim of the study was to determine the frequency of occurrence of antibodies participating in the development of endocrine diseases in patients with autoimmune haematopoietic disease, thus documenting the potential suitability of specific diagnostic and screening tests. MATERIAL AND METHODS: The study group consisted of 124 persons (men and women) with newly diagnosed pernicious anaemia (PA) and a control group (C) of 41 healthy people. Antibodies against: intrinsic factor (IFAb), gastric parietal cells (APCA), thyroid peroxidase (TPOAb), thyroglobulin (TgAb), adrenal cortex (AdrenalAb), and pituitary anterior lobe (PituitaryAb) were determined in the blood. RESULTS: 1. The risk of the presence of antibodies against endocrine glands in patients with PA can be classified in order: TPOAb and/or TgAb - 41.1%, TPOAb - 36.3%, TgAb - 25.0%, TPOAb and TgAb - 20.2%, AdrenalAb - 1.6%, PituitaryAb - 0.8%. 2. TPOAb and/or TgAb (mainly TPOAb) are more frequently present in patients with PA, who have IFAb and/or APCA. This correlation is most evident in patients with simultaneous occurrence of IFAb and APCA. 3. Among patients with PA, the simultaneous presence of antibodies IFAb and/or APCA with TPOAb and/or TgAb antibodies is most likely in women over 45 years of age. 4. In group C, 12% had at least one of two antithyroid antibodies (TgAb twice as often as TPOAb), and 2.4% had both. AdrenalAb and PituitaryAb are not found in healthy persons. CONCLUSIONS: In patients with PA, a screening for autoimmune thyroid disease is justified, which should first involve the determination of TPOAb (further TgAb) in the blood. The assessment of antithyroid antibodies should be recommended primarily to patients with PA, who have IFAb and/or APCA, and in particular those with concurrent IFAb and APCA.

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BACKGROUND: Pernicious anaemia (PA) is associated with increased gastric cancer risk, but the evidence is conflicting regarding the associated risk of other cancers. AIM: To systematically determine the incidence rates of gastro-intestinal cancers other than gastric cancers (GI-other-than-GC) and non-gastrointestinal cancers (non-GIC) in PA adults, globally and per tumour site, and the risk associated with PA for GI-other than GC and non-GIC. METHODS: Studies of PA patients reporting the incidence of GI-other-than-GCs and non-GICs were identified with MEDLINE (PubMed)-EMBASE (from first date available to April 2017). A meta-analysis of annual cancer incidence rates was performed. The outcome was the cumulative incidence of GI-other-than-GCs and non-GICs (ratio between the numbers of new cancer cases identified during the follow-up period and the number of PA patients) and the incidence rate expressed as the rate of events-per-time-unit (person-years). RESULTS: Of 82,257 PA patients, the pooled incidence rates/100 person-years for non-GCs and non-GICs of 0.27 (95% CI:0.16-0.42) and 0.23 (95% CI:0.22-0.25) were calculated by meta-analysis. Compared to the GLOBOCAN data for the general population from the countries of the included studies, the meta-analysis showed an overall relative risk (RR) of cancer in PA of 0.68 (95% CI:0.48-0.95). PA patients had a lower RR of colorectal, breast, liver, oesophageal, lung, thyroid, ovary, non-melanoma skin and kidney cancers but had a higher RR of biliary tract cancer (1.81:1.21-2.70), multiple myeloma (2.83:1.76-4.55), Hodgkin's lymphoma (3.0:1.35-6.68), non-Hodgkin's lymphoma (2.08: 1.58-2.75), and leukaemia (1.56:1.16-2.12). CONCLUSION: An overall lower RR of cancers-other-than-gastric-cancer in PA patients but an increased RR of biliary tract cancers and haematological malignancies was observed.

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BACKGROUND: Studies have found an association between proton pump inhibitor (PPI) use and Clostridium difficile infection. The purpose of this study was to determine whether the mechanism by which PPIs induce an increased risk of C. difficile infection is supported by the same mechanism acting in another cause of achlorhydria, pernicious anaemia. METHODS: Using a database of anonymised primary care records between 1990 and 2013, we selected exposed patients with a diagnosis of pernicious anaemia treated with vitamin B12 therapy. Each exposed patient was matched by age, gender and general practice to up to 10 controls. Cox regression analysis was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for C. difficile infection with pernicious anaemia, adjusted for potential confounders. RESULTS: We identified 45,467 exposed patients matched to 449,635 controls. The crude incidence rate of C. difficile infection was 1.85/1000 person-years for the exposed cohort and 1.09/1000 person-years for controls. Patients with pernicious anaemia had a greater risk of C. difficile infection than the controls (adjusted HR 1.57, 95% CI 1.40-1.76). CONCLUSIONS: Pernicious anaemia patients have an increased risk of C. difficile infection. This supports the theory that severe achlorhydria is the mechanism that increases the risk of C. difficile infection in long-term PPI users.