Adherence to Gluten-free Diet in a Celiac Pediatric Population Referred to the General Pediatrician After Remission.

OBJECTIVES: Assessment of adherence to gluten-free diet in celiac disease (CD) is generally recommended. Few data are available about consequences of transition from the referral center to the general pediatrician (GP) once remission is achieved. METHODS: Adherence was assessed in patients referred to the GP for an annual basis follow-up, called back for re-evaluation. Immunoglobulin A (IgA) antitissue transglutaminase (anti-tTG) antibodies and the Biagi score (BS) were determined at last follow-up at the referral center (V1), and at re-evaluation (V2). Patients were classified as adherent (BS 3-4, IgA anti-tTG <7 U/mL) and nonadherent (BS 0-2, IgA anti-tTG ≥7). Scores of adherence were correlated with personal and clinical data. RESULTS: We evaluated 200 patients. Overall, we found good adherence rates in 94.95% of patients at V1 and 83.5% at V2. IgA anti-tTG were negative in 100% at V1 and 96.97% at V2. BS is 3 to 4 in 94.5% at V1 and 84% at V2. Adherence at V2 was significantly worse than V1 (P < 0.001). No significant associations were found between scores of adherence and sex, symptoms and age at diagnosis, family history of CD, comorbidity, and diagnosis by endoscopy. Age 13 years or older represents a risk factor for lack of compliance at V1 (P = 0.02) and V2 (P = 0.04), and foreign nationality at V2 (P = 0.001). CONCLUSIONS: The BS, serology, and a clinical interview, integrated, are reliable tools for assessing pediatric adherence to gluten-free diet. We argue that referring patients to the GP after remission of CD is important, but the process must be improved and recommendations are required.

Autoimmune liver serology before and after successful treatment of chronic hepatitis C by direct acting antiviral agents.

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection is associated with a wide range of immunopathological manifestations, which are significantly improved by successful interferon-based treatment. There is paucity of data on the impact of interferon-free HCV clearance on immunopathological manifestations, which might be expected to disappear more frequently as compared to what reported in interferon-induced HCV-clearance. We have investigated liver autoimmune serology before and after interferon-free clearance of HCV by treatment with direct acting antiviral agents (DAA). METHOD: Patients within the Swiss Hepatitis C Cohort Study who underwent successful (SVR 12) HCV treatment with DAA were tested for autoimmune liver serology according to dedicated guidelines before and at least 6 months after end of treatment. RESULTS: A total of 235 patients were included; 62% males; median age 56 years; 27% with cirrhosis. Median time between end of DAA treatment and post-treatment serum sampling was 17 months. At least one autoantibody before treatment was found in 175 (74%) patients ; 32 (14%) were positive for 2 autoantibodies; no patient was positive for anti-SLA, anti-LC1 or typical AMA before or after DAA. ANA disappeared in 34%, SMA in 52% and anti-LKM1 in one of two patients after successful treatment, but, unexpectedly, one or more autoantibodies appeared in 27% of pre-treatment negative subjects. CONCLUSION: HCV clearance by DAA is associated with autoantibody disappearance in more than one third of the patients who were positive before treatment. However, the majority of the patients remain autoantibody-positive and 27% of those who were negative before treatment developed autoantibodies after DAA-induced HCV clearance. These data confirm that HCV infection is associated with autoimmunity and show that the autoimmune imprint persists after viral clearance by DAA, suggesting that long-term follow-up may be warranted.

Autoimmune liver disease serology in acute hepatitis E virus infection.

The etiology of autoimmune hepatitis (AIH) is unknown, though hepatotropic viruses may be potential triggers. Hepatitis E virus (HEV) infection, an increasingly recognized cause of acute hepatitis, has been misdiagnosed as AIH due to the occurrence of autoantibodies during its acute phase. It has also been suggested that HEV infection may lead to or unmask AIH. The HEV seroprevalence has been ascertained in patients with AIH, but the prevalence of AIH-related autoantibodies in patients with HEV infection has not been systematically tested. We aimed to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies, following the liver autoimmune serology guidelines of the International AIH Group. We tested 48 patients with acute HEV infection. Half of them had at least one autoantibody, 17% two autoantibodies. Anti-nuclear antibody (ANA) were detected in 16 (33%), anti-smooth muscle antibody (SMA) in 10 (21%), and anti-neutrophil cytoplasmic antibody (ANCA) in 7 (14.6%). Of note, two patients showed SMA with VG or VGT patterns and five had ANA with homogeneous appearance, both being typical of AIH type 1. Other AIH-specific autoantibodies were negative. Atypical anti-mitochondrial antibody, without evidence of primary biliary cholangitis, was positive in one patient, disappearing at follow-up. Follow-up (median 12 months) serum was available from seven autoantibody positive patients: two became negative, while five remained positive, although no patient developed AIH to date. In conclusion, autoantibodies are frequently present during acute HEV infection, indicating that HEV should always be excluded before diagnosing AIH. Importantly, a minority of patients with acute hepatitis E develops AIH-specific autoantibodies, and, though they did not progress to autoimmune liver disease in the short-term, they warrant long-term monitoring.

Tensegrity model hypothesis: may this paradigm be useful to explain hepatic and pancreatic carcinogenesis in patients with persistent hepatitis B or hepatitis C virus infection?

CONTEXT: Hepatitis B (HBV) and hepatitis C virus (HCV) possess well-known oncogenic properties and may promote carcinogenesis in liver. However antigens and replicative sequences of HBV/HCV have been also detected in different extra-hepatic tissues, including the pancreas. Although epidemiological studies and meta-analyses have recently suggested that HBV/HCV may be also risk factors for pancreatic cancer and several researches have investigated the possible mechanisms and intra-/extra-cellular paths involved in pancreatic and hepatic carcinogenesis, to date, these complex processes remain largely unexplained. OBJECTIVES: In our paper, we aimed to propose a comprehensive and qualitative hypothetical model, describing how HBV/HCV may exert their oncogenic role. METHODS: We performed a systematic research of scientific literature, by searching MEDLINE, the Cochrane Library and EMBASE databases. The used keywords were: "chronic HBV/HCV", "pancreatic cancer", "liver carcinoma", "carcinogenesis mechanisms", "tensional integrity", "cytoskeleton", and "extracellular matrix". RESULTS: Taking advantage from available studies, we suggest an unifying hypothesis based on results and data, obtained from different areas of research. In particular we considered the well-defined model of tensional integrity and correlated it to changes induced by HBV/HCV in viscoelastic properties/stiffness of cellular/extracellular microenvironments. These events perturb the tightly-regulated feedback loop, which usually couples the intracellular-generated forces to substrate rigidity of extracellular compartments. Therefore, such a change strongly affects intracellular functions and cellular fate, by promoting a substantial deregulation of critical intracellular biochemical activities and genome expression. CONCLUSIONS: Our hypothesis might provide for the first time a reliable system, which correlates tensional integrity model with intra-/extra-cellular modifications, occurring in liver and pancreas during HBV/HCV-induced carcinogenesis. This approach might improve our understanding of pathogenetic mechanisms involved in the development of pancreatic and hepatic carcinogenesis , enhancing the possibility of their treatment. Furthermore, should the usefulness of this model be definitively confirmed, it might be also helpful to extend its field of application to other viruses-related cancers.

Antitissue transglutaminase antibodies' normalization after starting a gluten-free diet in a large population of celiac children-a real-life experience.

INTRODUCTION: Few data are available regarding the trend of IgA anti-transglutaminase antibodies (TGA-IgA) in children with celiac disease (CD) on a gluten-free diet (GFD). Our aim is to examine the normalization time of CD serology in a large pediatric population, and its predictors. MATERIAL AND METHODS: We retrospectively evaluated the normalization time of TGA-IgA and its predictive factors (age, sex, ethnicity, symptoms, associated diabetes/thyroiditis, Marsh stage, TGA-IgA and endomysial antibody levels at diagnosis, diet adherence), in 1024 children diagnosed from 2000 to 2019 in three pediatric Italian centers, on a GFD. RESULTS: TGA-IgA remission was reached in 67,3%, 80,7%, 89,8% and 94,9% after 12, 18, 24 and 36 months from starting a GFD, respectively (median time = 9 months). TGA-IgA >10´upper limit of normal at diagnosis (HR = 0.56), age 7-12 years old (HR = 0.83), poor compliance to diet (HR = 0.69), female sex (HR = 0.82), non-Caucasian ethnicity (HR = 0.75), and comorbidities (HR = 0.72) were independent factors significantly associated with longer time to normalization. CONCLUSIONS: Our population is the largest in the literature, with the majority of patients normalizing CD serology within 24 months from starting a GFD. We suggest a special attention to patients with comorbidities, language barriers or age 7-12 years for a proper management and follow-up.

Diagnostic accuracy of anti-phospholipase A2 receptor (PLA2R) antibodies in idiopathic membranous nephropathy: an Italian experience.

BACKGROUND: Autoantibodies against-phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (iMN). Enzyme-linked immunosorbent assay (ELISA) is becoming the preferred method in many laboratories for the determination of anti-PLA2R antibodies, because it provides quantitative results, and is not prone to subjective interpretation, as is the case with indirect immunofluorescence assay. METHODS: The purpose of our study was to determine the diagnostic performance of serum PLA2R antibodies detected by commercially available ELISA in a large Italian multicenter cohort of patients with biopsy-proven iMN and in patients with other renal diseases, with special focus on evaluating the optimal cut-off value to discriminate positive and negative results. A total of 495 consecutive patients were recruited. Renal biopsies were performed in all patients, and blood samples were taken before the initiation of immunosuppressive treatment. RESULTS: According to the clinical diagnosis and to kidney biopsy, 126 patients were diagnosed with iMN and 369 had other non-membranous nephropathies. Anti-PLA2R autoantibodies were detected using a commercial anti-PLA2R ELISA. At a cut-off value of 20 relative units (RU)/ml indicated by the manufacturer for positive classification, sensitivity was 61.1% and specificity 99.7%. At a cut-off value of 14 RU/ml indicated by the manufacturer for borderline results, sensitivity was 63.5% and specificity remained the same (99.7%). At a cut-off of 2.7 RU/ml, selected as the optimal cut-off on the basis of ROC curve analysis, sensitivity was 83.3% and specificity 95.1%. The best overall efficiency of the test was observed at 2.7 RU/ml; however, the highest positive likelihood ratio and diagnostic odds ratio were achieved at 14 RU/ml. A cut-off threshold higher than 14 RU/ml or lower than 2.7 RU/ml entailed worse test performance. CONCLUSION: Depending on the clinical use (early diagnosis or as a support to confirm clinical diagnosis), nephrologists may take advantage of this evidence by choosing the most convenient cut-off. However, renal biopsy remains mandatory for the definitive diagnosis of iMN and for the assessment of disease severity.

COVID-19 and Immunological Dysregulation: Can Autoantibodies be Useful?

Coronavirus disease 2019 (COVID-19) is often associated with interstitial pneumonia. However, there is insufficient knowledge on the presence of autoimmune serological markers in patients with COVID-19. We analyzed the presence and role of autoantibodies in patients with COVID-19-associated pneumonia. We prospectively studied 33 consecutive patients with COVID-19, 31 (94%) of whom had interstitial pneumonia, and 25 age-matched and sex-matched patients with fever and/or pneumonia with etiologies other than COVID-19 as the pathological control group. All patients were tested for the presence of antinuclear antibodies (ANAs), anti-antiphospholipid antibodies, and anti-cytoplasmic neutrophil antibodies (ANCAs). Clinical, biochemical, and radiological parameters were also collected. Fifteen of 33 patients (45%) tested positive for at least one autoantibody, including 11 who tested positive for ANAs (33%), 8 who tested positive for anti-cardiolipin antibodies (immunoglobulin (Ig)G and/or IgM; 24%), and 3 who tested positive for anti-ß2-glycoprotein antibodies (IgG and/or IgM; 9%). ANCA reactivity was not detected in any patient. Patients that tested positive for auto-antibodies had a significantly more severe prognosis than other patients did: 6 of 15 patients (40%) with auto-antibodies died due to COVID-19 complications during hospitalization, whereas only 1 of 18 patients (5.5%) who did not have auto-antibodies died (P = 0.03). Patients with poor prognosis (death due to COVID-19 complications) had a significantly higher respiratory rate at admission (23 breaths per minute vs. 17 breaths per minute; P = 0.03) and a higher frequency of auto-antibodies (86% vs. 27%; P = 0.008). In conclusion, auto-antibodies are frequently detected in patients with COVID-19 possibly reflecting a pathogenetic role of immune dysregulation. However, given the small number of patients, the association of auto-antibodies with an unfavorable prognosis requires further multicenter studies.