Marco Vincenzo Lenti

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.

New insights into immune mechanisms underlying autoimmune diseases of the gastrointestinal tract.

Recent progresses in the immune mechanisms implicated in chronic inflammatory disorders have led to a more in-depth knowledge of the pathogenesis of autoimmune diseases of the gastrointestinal tract, including autoimmune atrophic gastritis, celiac disease, autoimmune enteropathy and ulcerative colitis. While the pathogenic role of specific circulating autoantibodies, i.e., respectively anti-parietal cell, anti-tissue transglutaminase, anti-enterocyte and anti-neutrophil cytoplasmic, is still controversial, some common T-cell mediated mechanisms for inflammation - increase in T helper cell type 1/type 17 pro-inflammatory cytokines- or losing self-tolerance-abnormal regulatory T cell function - are recognized as crucial mediators of the tissue damage causing atrophy of the stomach mucosa in autoimmune atrophic gastritis, villous flattening of the small bowel in celiac disease and autoimmune enteropathy, and mucosal ulceration of the colon in ulcerative colitis. This review deals with novel advances in the immunological bases of the aforementioned autoimmune gastrointestinal disorders, and it also highlights immune mechanisms of progression from chronic inflammation to cancer and implications for new therapeutic targets.

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.

The Time Course of Diagnostic Delay in Inflammatory Bowel Disease Over the Last Sixty Years: An Italian Multicentre Study

Background and Aims Inflammatory bowel disease [IBD] patients are still under-diagnosed or diagnosed with serious delay. We examined whether diagnostic delay [DD] in IBD has changed over the last 60 years, and explored the risk factors of longer DD. Methods In total, 3392 IBD patients recorded in the registry of four IBD Italian centres were divided according to the year of diagnosis into a historical cohort [HC: 1955-84] and modern cohort [MC: 1985-2014]. DD, i.e. time lapse between onset of symptoms indicative of IBD and definitive diagnosis, was divided into four sub-periods [0-6, 7-12, 13-24, >24 months], which were correlated with age and disease location/behaviour at diagnosis. Results Median DD in IBD was 3.0 months, it was significantly [P < 0.0001] higher in Crohns disease [CD] [7.1 months] than in ulcerative colitis [UC] [2.0 months], and did not differ either between the HC and the MC or over the last three decades. However, the proportion of patients with a DD>24 months was significantly [P < 0.0001] higher in the HC [26.0%] than in the MC [18.2%], and the same trend was evident over the last three decades [1985-94: 19.9%; 1995-2004: 16.4%; 2005-14: 13.9%; P = 0.04]. At logistic regression analysis, age at diagnosis >40 years (CD: odds ratio 1.73, 95% confidence interval [CI] 1.31-2.28, P < 0.0001; UC: 1.41, 95% CI 1.02-1.96, P = 0.04) and complicated disease at CD diagnosis [1.39, 95% CI 1.06-1.82, P = 0.02] were independently associated with a DD>24 months. Conclusions DD duration has not changed over the last 60 years in Italy, but the number of IBD patients with a longer DD significantly decreased. Older age at diagnosis and a complicated disease at CD diagnosis are risk factors for longer DD.

The Italian Society of Internal Medicine choosing wisely campaign

Appropriateness is one of the critical aspects of medicine. For this reason, the Italian Society of Internal Medicine (SIMI) decided to adhere to the Choosing Wisely Campaign. A bottom-up approach was chosen. All the recommendations published in the US and Canadian Choosing Wisely campaign have been screened, and an e-mail was sent to all the SIMI members for new suggestions. The thirty interventions that were judged as the highest priority by a committee were sent to all the SIMI members for voting. The first procedures selected were then revised, and constituted the five points of the SIMI choosing wisely campaign. The identified procedures were: (1) avoid prescribing bed rest unless an acceptable indication exists. Promote early mobilization; (2) Do not perform a D-dimer test without a precise indication; (3) Do not prescribe long term intravenous antibiotic therapy in the absence of symptoms; (4) Do not indefinitely prescribe proton pump inhibitors in the absence of specific indications; (5) Do not place, or leave in place, peripherally inserted central catheters for patient’s or provider’s convenience. Four of these points were not present in any other campaign, while one, the fifth, was already present. The bottom-up approach of the SIMI “Choosing Wisely” campaign favored the identification of different priorities compared to other campaigns. Future studies should now evaluate if the application of these “not-to-do” recommendations will be associated with an improvement of clinical outcome and a subsequent direct and indirect health care cost reduction.

The challenging diagnosis of autoimmune atrophic gastritis

We read with interest the article by Zhang et al. investigating 320 patients who were diagnosed with autoimmune atrophic gastritis (AAG) within a large cohort of 97,341 Chinese patients referred for an upper gastrointestinal endoscopy, over a 8-year period [1]. The Authors made a comprehensive study, analyzing laboratory tests (cell blood count, vitamin B12 status), serum autoantibodies and endoscopic findings of patients with AAG, with an annual detection rate of 0.9%. This is one of the largest cohorts ever described in an Asiatic population. However, the clinical findings and the inclusion criteria used by the Authors raise a few issues that should be clarified. Over the last two decades, there has been an increasing awareness and attention on AAG pathogenesis [2] and its clinical [3], laboratory [4–6] and histopathological [7] diagnosis. It is known that AAG has a wide clinical spectrum, which encompasses haematological, gastroenterological and neurological manifestations [3]. Furthermore, AAG is surely associated with autoimmune diseases, namely autoimmune thyroid diseases [8] and type I diabetes mellitus [9], but presumably also with celiac disease, connective tissue disorders and others [3]. Zhang et al. reported a rather high prevalence of anti-thyroid (80.6%), anti-nuclear (29.2%) and anti-mitochondrial antibodies (3.5%). These remarkable results warrant a better awareness about these possible associations; however, we wonder how many of those patients might also have a positive serology for celiac disease. The Authors depict variable haematological findings that might also be explained by this latter condition. Moreover, the Authors used potentially misleading diagnostic criteria, also including patients with multifocal atrophic gastritis and with no AAG specific autoantibodies (defining these latter patients as affected by ‘probable’ AAG). Anti-gastric parietal cell antibodies (PCA) marked the turning point in serological diagnosis of AAG and there is evidence that they should be tested through an enzyme-linked immunosorbent assay, which is the most accurate method (81% specificity, 90% sensitivity) [4,6]. Also, it is known that PCA may rise, peak and fall over time in the natural history of AAG [8] and may disappear in the late stages. For these reasons, in case of a clear corpus-restricted atrophic gastritis and no evidence of active H. pylori infection, even in the absence of PCA, we can still diagnose AAG with reasonable assurance. In case of further doubts, the detection of anti-intrinsic factor antibodies could increase PCA diagnostic accuracy [4]. On the contrary, multifocal atrophic gastritis (both corpus and antrum atrophy) in the absence of autoantibodies should be considered as a different disease, possibly with a higher risk of developing gastric cancer according to the OLGA staging [7]. Finally, chromogranin A immunostaining should be an integral part of the pathological assessment as it has been proven to be useful for addressing diagnosis of AAG, especially in its early phase [7,10]. To conclude, AAG is a multifaceted disease whose diagnosis should rely on clinical and laboratory suspicious and histopathological confirmation. Hence, more studies are needed focusing on a better characterization of all these aspects, in order to overcome all the aforementioned limitations.

Detection of Active Epstein–Barr Virus Infection in Duodenal Mucosa of Patients With Refractory Celiac Disease

Refractory celiac disease is characterized by mucosal damage in patients with celiac disease despite a gluten-free diet. Little is known about the mechanisms that cause persistent intestinal inflammation in these patients. We performed a case-control study of 17 consecutive patients diagnosed with refractory celiac disease from 2001 through 2014 (median age, 51 y; 10 women) and 24 patients with uncomplicated celiac disease (controls) to determine whether refractory disease is associated with infection by lymphotropic oncogenic viruses. We performed real-time PCR analyses of duodenal biopsy samples from all patients to detect Epstein-Barr virus (EBV), human herpesvirus-8, and human T-cell lymphotropic virus-I, -II, or -III. We used in situ hybridization and immunohistochemical analyses to identify infected cells and viral proteins. We did not detect human herpesvirus-8 or human T-cell lymphotropic viruses in any of the biopsy specimens. However, 12 of 17 (70.5%) biopsy specimens from patients with refractory celiac disease were positive for EBV, compared with 4 of 24 (16.6%) biopsy specimens from controls (P < .001). EBV was detected in inflammatory cells and enterocytes. An analysis of latency- and replication-associated proteins confirmed active infection. Further studies are needed to determine whether EBV infection contributes to the pathogenesis of refractory celiac disease and enteropathy-associated T-cell lymphoma.

A consensus for the development of a vector model to assess clinical complexity

The progressive rise in multimorbidity has made management of complex patients one of the most topical and challenging issues in medicine, both in clinical practice and for healthcare organizations. To make this easier, a score of clinical complexity (CC) would be useful. A vector model to evaluate biological and extra-biological (socio-economic, cultural, behavioural, environmental) domains of CC was proposed a few years ago. However, given that the variables that grade each domain had never been defined, this model has never been used in clinical practice. To overcome these limits, a consensus meeting was organised to grade each domain of CC, and to establish the hierarchy of the domains. A one-day consensus meeting consisting of a multi-professional panel of 25 people was held at our Hospital. In a preliminary phase, the proponents selected seven variables as qualifiers for each of the five above-mentioned domains. In the course of the meeting, the panel voted for five variables considered to be the most representative for each domain. Consensus was established with 2/3 agreement, and all variables were dichotomised. Finally, the various domains were parametrized and ranked within a feasible vector model. A Clinical Complexity Index was set up using the chosen variables. All the domains were graphically represented through a vector model: the biological domain was chosen as the most significant (highest slope), followed by the behavioural and socio-economic domains (intermediate slope), and lastly by the cultural and environmental ones (lowest slope). A feasible and comprehensive tool to evaluate CC in clinical practice is proposed herein.

Infliximab Therapeutic Drug Monitoring Changes Clinical Decisions in a Virtual Biologics Clinic for Inflammatory Bowel Disease.

Background: Virtual biologics clinics are often used to review patients with inflammatory bowel disease receiving biological therapy, with decisions whether to continue, switch, or stop therapy made based on review of symptoms, disease history, and investigations. We aimed to investigate whether therapeutic drug monitoring of infliximab (IFX) trough levels and anti-drug antibodies influences decision making within a virtual biologics clinic. Methods: For all patients with inflammatory bowel disease receiving IFX maintenance therapy, 2 decisions were recorded in a preset format. The first decision was based on assessment of clinical details, with clinicians blinded to IFX trough levels and anti-drug antibodies. The second decision was made after unblinding of these data. Results: Among 191 patients (mean age 40 years; 106 (55.5%) male), IFX trough levels were sub-therapeutic in 53 (27.7%) (<2 mg/L), therapeutic in 100 (52.4%), and supra-therapeutic in 38 (19.9%) (>6 mg/L). Anti-drug antibodies were detected in 58 (30.4%), and were >50 AU/mL in 26 (13.6%). Blinded treatment decisions were changed on unblinding these data in 56 cases (29.3%; P < 0.0001). Knowledge of these data led to 7 (3.7%) patients receiving intensified IFX, whereas 33 (17.3%) patients were able to either dose de-escalate or stop IFX. Conclusions: Basing decisions on therapeutic drug monitoring, rather than clinical acumen alone, led to a change in almost one-third of decisions made, offering considerable cost savings and reducing exposure to potentially toxic therapies. Routine therapeutic drug monitoring should be considered an integral part of annual biologics assessment (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B629).

Acquired von Willebrand syndrome in inflammatory bowel disease

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder resulting from quantitative and/or qualitative defect of von Willebrand factor (VWF). VWF is a high-molecular-weight multimeric glycoprotein, synthesized and released by vascular endothelial cells and megakaryocytes that play an important role in platelet-endothelial cell interaction and stabilizing the factor VIII (FVIII) coagulation protein [1]. AVWS has been mostly associated with monoclonal gammopathy of uncertain significance, lymphoproliferative, myeloproliferative and neoplastic disorders, more rarely with hypothyroidism, uremia, pancreatitis, liver cirrhosis and autoimmune disorders (i.e. systemic lupus erythematosus) [2,3]. The pathogenesis of AVWS may be various in different disorders, and it includes autoantibodies, sequestration of high-molecular-weight multimers through adsorption to cells, proteolytic cleavage and decreased synthesis. In bleeding patients, von Willebrand disease (VWD) is the most frequent hereditary coagulopathy, and it should be always considered. Once low levels of VWF are detected, it is crucial to distinguish between AVWS and congenital VWD in order to apply the best treatment. However, laboratory routine tests do not allow differentiation between these two forms. In favour of AVWS diagnosis are late onset of bleeding symptoms, negative family history for bleeding disorders, presence of inhibitors or VWFbinding antibodies (although they are detected with low frequency), spontaneous remission and short-lived response to VWF-containing concentrates [2,3]. Up to now, AVWS has been reported in association with inflammatory bowel disease (IBD) in three cases, two with ulcerative colitis and one with Crohn’s disease [4–6]. This is in contrast with a number of previous studies showing increased circulating VWF levels in active IBD patients as a consequence of vascular inflammation and injury [7–9]. We here report three cases of patients with IBD, one with Crohn’s disease and two with ulcerative colitis, who turned out to be affected by AVWS. Demographic, clinical and laboratory parameters are shown in Table 1. Patient 1, with a previous history of hypertension and stroke, was diagnosed as affected by ileocolonic Crohn’s disease in 2001. He was referred to our Centre in 2007 for a clinical relapse of Crohn’s disease characterized by cramping abdominal pain and fever. He did not follow any specific treatment for Crohn’s disease. Both imaging and endoscopy confirmed the presence of a stricture of the terminal ileum, and thus the patient underwent surgical resection. At that time, prothrombin time (PT) and activated partial thromboplastin time (aPTT) were normal. After surgery, the patient was put under treatment with oral mesalazine and cyclical antibiotics (metronidazole and ciprofloxacin). In 2010, at the age of 75 years, the patient had many episodes of nose bleeding treated with cauterization and hematomas after minimal contusions. Specific blood tests revealed prolonged aPTT associated with a defect of VWF:Ag, VWF:RCo and FVIII (Table 1). Kinetics of VWF after infusion of 30 IU Kg 1 plasma-derived VWF-containing FVIII concentrates was consistent with the diagnosis of AVWS as confirmed by the short halflife of infused factor (Fig. 1, Pt.1). From the diagnosis of AVWS to now, the patient has not experienced further clinical relapses or postsurgical recurrences of Crohn’s disease, although he has been poorly adherent to the cyclical antibiotic treatment. Moreover, he has maintained normal VWF/FVIII levels, which have been monitored every 6 months in the last 6 years. Patient 2, with a previous history of breast adenocarcinoma treated with right mastectomy and chemotherapy was referred to our Centre in 2001 for hematochezia, diarrhoea and abdominal pain. Colonoscopy highlighted mild inflammation with granularity, friability and erosions confined to the left colon, and histology confirmed the diagnosis of left-sided ulcerative colitis. The patient was then treated with both oral and topical formulations of mesalazine with clinical benefit. At that time, blood Correspondence: Antonio Di Sabatino, Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Piazzale Golgi 19, 27100 Pavia, Italy. Tel.: +39 0382 501596; fax +39 0382 502618; e-mail: a.disabatino@smatteo.pv.it