Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.

The Intertwining Roads between Psychological Distress and Gut Microbiota in Inflammatory Bowel Disease.

Inflammatory bowel disease represents one of the most life-altering gastrointestinal pathologies, with its multifactorial nature and unclear physiopathology. The most relevant clinical forms, ulcerative colitis and Crohn's disease, clinically manifest with mild to severe flares and remission periods that alter the patient's social, familial and professional integration. The chronic inflammatory activity of the intestinal wall determines severe modifications of the local environment, such as dysbiosis, enteric endocrine, nervous and immune system disruptions and intestinal wall permeability changes. These features are part of the gastrointestinal ecosystem that modulates the bottom-to-top signaling to the central nervous system, leading to a neurobiologic imbalance and clinical affective and/or behavioral symptoms. The gut-brain link is a bidirectional pathway and psychological distress can also affect the central nervous system, which will alter the top-to-bottom regulation, leading to possible functional digestive symptoms and local inflammatory responses. In the middle of this neuro-gastrointestinal system, the microbiome is a key player, as its activities offer basic functional support for both relays. The present article presents current scientific information that links the pathophysiology and clinical aspects of inflammatory bowel disease and psychiatric symptomatology through the complex mechanism of the gut-brain axis and the modulatory effects of the gut microbiota.

Significant Differences in IBD Care and Education across Europe: Results of the Pan-European VIPER Survey.

BACKGROUND: Inflammatory bowel disease (IBD) care and education might differ around Europe. Therefore, we conducted this European Variation In IBD PracticE suRvey (VIPER) to investigate potential differences between countries. METHODS: This trainee-initiated survey, run through SurveyMonkey®, consisted of 47 questions inquiring basic demographics, IBD training, and clinical care. Results were compared according to gross domestic product (GDP) per capita, for which countries were divided into 2 groups (low/high income, according to the World Bank). RESULTS: The online survey was completed by 1,285 participants from 40 European countries, with a majority of specialists (65.3%) working in academic institutions (50.4%). Significant differences in IBD-specific training (55.9% vs. 38.4%), as well as availability of IBD units (58.4% vs. 39.7%) and multidisciplinary meetings (73.2% vs. 40.1%), were observed between respondees from high and low GDP countries (p < 0.0001). In high GDP countries, IBD nurses are more common (85.9% vs. 36.0%), also mirrored by more nurse-led IBD clinics (40.6% vs. 13.7%; p < 0.0001). IBD dieticians (33.4% vs. 16.5%) and psychologists (16.8% vs. 7.5%) are mainly present in high GDP countries (p < 0.0001). In the current COVID era, telemedicine is available in 73.2% versus 54.1% of the high/low GDP countries, respectively (p < 0.0001). Treat-to-target approaches are implemented everywhere (85.0%), though access to biologicals and small molecules differs significantly. CONCLUSION: Much variability in IBD practice exists across Europe, with marked differences between high and low GDP countries. Further work is required to help address some of these inequalities, aiming to improve and standardize IBD care and training across Europe.

Automated Retinal Vessel Analysis Based on Fundus Photographs as a Predictor for Non-Ophthalmic Diseases-Evolution and Perspectives.

The study of retinal vessels in relation to cardiovascular risk has a long history. The advent of a dedicated tool based on digital imaging, i.e., the retinal vessel analyzer, and also other software such as Integrative Vessel Analysis (IVAN), Singapore I Vessel Assessment (SIVA), and Vascular Assessment and Measurement Platform for Images of the Retina (VAMPIRE), has led to the accumulation of a formidable body of evidence regarding the prognostic value of retinal vessel analysis (RVA) for cardiovascular and cerebrovascular disease (including arterial hypertension in children). There is also the potential to monitor the response of retinal vessels to therapies such as physical activity or bariatric surgery. The dynamic vessel analyzer (DVA) remains a unique way of studying neurovascular coupling, helping to understand the pathogenesis of cerebrovascular and neurodegenerative conditions and also being complementary to techniques that measure macrovascular dysfunction. Beyond cardiovascular disease, retinal vessel analysis has shown associations with and prognostic value for neurological conditions, inflammation, kidney function, and respiratory disease. Artificial intelligence (AI) (represented by algorithms such as QUantitative Analysis of Retinal vessel Topology and siZe (QUARTZ), SIVA-DLS (SIVA-deep learning system), and many others) seems efficient in extracting information from fundus photographs, providing prognoses of various general conditions with unprecedented predictive value. The future challenges will be integrating RVA and other qualitative and quantitative risk factors in a unique, comprehensive prediction tool, certainly powered by AI, while building the much-needed acceptance for such an approach inside the medical community and reducing the "black box" effect, possibly by means of saliency maps.

Functional Gastrointestinal Disorders with Psychiatric Symptoms: Involvement of the Microbiome-Gut-Brain Axis in the Pathophysiology and Case Management.

Functional Gastrointestinal Disorders have been an important cause of poor life quality in affected populations. The unclear etiology and pathophysiological mechanism alter the clinical evolution of the patient. Although a strong connection with psychological stress has been observed, it was not until recently that the gut-brain axis involvement has been revealed. Furthermore, the current literature not only promotes the gut-brain axis modulation as a therapeutical target for functional digestive disorders but also states that the gut microbiome has a main role in this bi-directional mechanism. Psychiatric symptoms are currently recognized as an equally important aspect of the clinical manifestation and modulation of both the digestive and central nervous systems and could be the best approach in restoring the balance. As such, this article proposes a detailed description of the physiology of the microbiome-gut-brain axis, the pathophysiology of the functional gastrointestinal disorders with psychiatric symptoms and current perspectives for therapeutical management, as revealed by the latest studies in the scientific literature.

Magnesium-A Potential Key Player in Inflammatory Bowel Diseases?

The altered magnesium status in inflammatory bowel disease (IBD) patients may have a significant clinical imprint considering its role in cell signaling and genomic stability, as well as its involvement in IBD patients' fatigue. Our study pioneers the investigation of magnesium hair concentration patterns in an adult population of IBD patients. The hair magnesium concentration in IBD patients is compared to healthy controls in order to identify correlations between the magnesium status and relevant parameters related to disease activity, psychological status, and sleep quality. We report a significantly lower hair magnesium concentration within the IBD group compared to healthy controls (95%CI: 0.006-0.062; p = 0.017) and lower levels in CD compared to UC (95%CI: -0.061--0.002; p = 0.038). We identified a borderline statistical significance between the hair magnesium concentration and UC disease activity (95%CI; -0.679-0.008; p = 0.055) and a significantly lower magnesium concentration in patients who reported increased sleep latency (95%CI -0.65--0.102; p = 0.011) or decreased sleep duration (95%CI -0.613--0.041; p = 0.028). Our results advance several hypotheses with substantial clinical impact to be confirmed in future studies. Magnesium levels appear to be modified in IBD patients, which suggests it either plays a primary role in disease pathophysiology or a is result of the disease's evolution. Magnesium could be used in predictive models for clinical/subclinical disease activity. Moreover, magnesium supplementation may improve IBD evolution and sleep quality for patients with a deficit of this mineral. However, confirmatory evidence-based studies are needed to generate specific dosing, time of supplementation, and optimum monitoring of magnesium status in IBD patients.

Could the burden of pancreatic cancer originate in childhood?

The presence of pancreatic cancer during childhood is extremely rare, and physicians may be tempted to overlook this diagnosis based on age criteria. However, there are primary malignant pancreatic tumors encountered in pediatric patients, such as pancreatoblastoma, and tumors considered benign in general but may present a malignant potential, such as the solid pseudo-papillary tumor, insulinoma, gastrinoma, and vasoactive intestinal peptide secreting tumor. Their early diagnosis and management are of paramount importance since the survival rates tend to differ for various types of these conditions. Many pediatric cancers may present pancreatic metastases, such as renal cell carcinoma, which may evolve with pancreatic metastatic disease even after two or more decades. Several childhood diseases may create a predisposition for the development of pancreatic cancer during adulthood; hence, there is a need for extensive screening strategies and complex programs to facilitate the transition from pediatric to adult healthcare. Nevertheless, genetic studies highlight the fact the specific gene mutations and family aggregations may be correlated with a special predisposition towards pancreatic cancer. This review aims to report the main pancreatic cancers diagnosed during childhood, the most important childhood diseases predisposing to the development of pancreatic malignancies, and the gene mutations associates with pancreatic malignant tumors.

Clostridioides difficile Infection in Patients with Chronic Kidney Disease: A Systematic Review.

Clostridioides difficile infection (CDI) is a health issue of utmost significance in Europe and North America, due to its high prevalence, morbidity, and mortality rate. The clinical spectrum of CDI is broad, ranging from asymptomatic to deadly fulminant colitis. When associated with chronic kidney disease (CKD), CDI is more prevalent and more severe than in the general population, due to specific risk factors such as impaired immune system, intestinal dysmotility, high antibiotic use leading to disturbed microbiota, frequent hospitalization, and PPI use. We performed a systematic review on the issue of prevention and treatment of CDI in the CKD population, analysing the suitable randomized controlled cohort studies published between 2000 and 2021. The results show that the most important aspect of prevention is isolation and disinfection with chlorine-based solution and hydrogen peroxide vapour to stop the spread of bacteria. In terms of prevention, using Lactobacillus plantarum (LP299v) proved to be more efficient than disinfection measures in transplant patients, leading to higher cure rates and less recurrent episodes of CDI. Treatment with oral fidaxomycin is more effective than with oral vancomycin for the initial episode of CDI in CKD patients. Faecal microbiota transplantation (FMT) is more effective than vancomycin in recurrent CDI in CKD patients. More large-sample RCTs are necessary to conclude on the best treatment and prevention strategy of CDI in CKD patients.

Risk Factors for Extraintestinal Manifestations in Inflammatory Bowel Diseases - Data from the Romanian National Registry.

BACKGROUND AND AIMS: Identifying the risk factors for extraintestinal manifestations (EIMs) in inflammatory bowel diseases (IBD) may optimize the therapeutic decision. We aimed to assess the prevalence of EIMs in IBD patients in Romania and to determine the risk factors. METHODS: We analyzed 2,626 patients registered in the Romanian IBD Prospect National Registry. We performed a descriptive cross-sectional study to assess the point prevalence of EIMs, calculating global prevalence and analyzing the different types of EIMs and their respective frequencies were carried out. Demographic and clinical risk factors were researched as possible predictors for EIMs development, based on the results of the univariate and multivariate logistic regression analysis. RESULTS: The overall point prevalence of EIMs was 16.3%. A significantly higher frequency of EIMs in Crohn's disease (CD) was noted in comparison to ulcerative colitis (UC) and IBD unclassified (IBDU) (23.2% vs 11.3% and 16.3%, respectively, p<0.001). The most frequent type of EIM was peripheral arthropathy (8.3%), significantly associated with CD (p<0.001). Univariate analysis highlighted the significant independent common predictive risk factors for EIMs, in both CD and UC patients: female gender, patient's urban area of origin, anemia, hypoalbuminemia, and high level of C-reactive protein (CRP), while significant independent IBD phenotype-related risk factors were ileocolonic location and concomitant involvement of upper gastrointestinal tract for CD, non-smoker status and both moderate and severe disease activity for UC (p<0.05). Multivariate analysis determined that female CD patients with moderate or severe disease activity, with other than isolated ileal disease, and female UC patients with moderate or severe extensive colitis are the most likely to develop EIMs. CONCLUSIONS: IBD patients are experiencing EIMs in a large proportion, with higher rates for CD. As EIMs negatively affect patient outcomes, foreseeing the risk by identifying independent and associated predictive factors could be a first step to optimal work-up and treatment.

Hair EDX Analysis-A Promising Tool for Micronutrient Status Evaluation of Patients with IBD?

Micronutrient deficiencies can arise in various conditions, including inflammatory bowel diseases (IBD), and diagnosing these deficiencies can be challenging in the absence of specific clinical signs. The aim of this study was to evaluate the status of various trace elements hair concentration in IBD patients compared to a healthy control group and to identify potential correlations between the micronutrient status and relevant parameters related to disease activity. The concentrations of iron, magnesium, calcium, zinc, copper, manganese, selenium and sulfur in the hair of 37 IBD patients with prior diagnosed IBD (12 Crohn's disease and 25 ulcerative colitis) and 31 healthy controls were evaluated by Energy Dispersive X-Ray spectroscopy (EDX). Significant differences in hair concentration profile of studied trace elements were identified for IBD patients compared to healthy controls. A significantly decreased hair concentration of iron, magnesium, calcium and selenium and a significantly increased sulfur hair concentration were observed in IBD patients at the time of evaluation. A decreased hair calcium concentration (r = -0.772, p = 0.003) and an increased sulfur concentration (r = 0.585, p = 0.046) were significantly correlated with disease activity. Conclusion: Hair mineral and trace elements evaluation may contribute to a proper evaluation of their status in IBD patients and improving the management of nutritional status of IBD patients.

Romanian Guidelines for Nonpharmacological Therapy of IBS.

BACKGROUND AND AIMS: The nonpharmacological therapy in irritable bowel syndrome (IBS) is expanding rapidly. Practitioners and medical educators need to be aware of progress and changes in knowledge of this topic. The Romanian Society of Neurogastroenterology aimed to create guidelines based on best evidence on the use of nonpharmacological therapy in IBS. METHODS: A group of experts was constituted. This was divided in eleven subgroups dedicated to eleven categories of nonpharmacological therapy. The subgroups searched the literature and formulated statements and recommendations. These were submitted to vote in order to obtain consensus. RESULTS: The outcome of this activity is represented by the guidelines of the Romanian Society of Neurogastroenterology, presented in this paper. The recommendations are seen as complementary to the pharmacological therapy and are not intended to recommend avoiding pharmacological drugs. CONCLUSIONS: These guidelines were elaborated by a Delphi process and represent a useful tool for physicians managing patients with IBS.

Romanian National Guideline on Translating Fecal Microbiota Transplantation Applications related to Clostridioides difficile Infections into the Local Clinical Practice.

Fecal microbiota transplantation involves the infusion of intestinal microorganisms via the transfer of a stool from a healthy individual into a diseased individual, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for the treatment of refractory Clostridioides difficile infection. At present, recurrent Clostridioides difficile infection is the only indication supported by solid scientific evidence. Regulations by healthcare authorities vary among different countries. Considering that Romania does not have an available national guideline to offer standardization, this paper aimed to create a national fecal microbiota transplantation guideline concerning indications, techniques and donor screening, developed by international and local scientific working groups.

Split-dose or hybrid nonsteroidal anti-inflammatory drugs and N-acetylcysteine therapy for prevention of post-retrograde cholangiopancreatography pancreatitis.

BACKGROUND: Despite significant technical and training improvements, the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) has not significantly dropped. Although many studies have evaluated the efficacy of various agents, e.g. nonsteroidal anti-inflammatory drugs, octreotide, antioxidants, administered via various dosages, routes (oral, intrarectal or parenteral), and schedules (before or after the procedure), the results have been conflicting. AIM: To evaluate efficacy of three pharmacologic prophylactic methods for prevention of PEP. METHODS: In this prospective, single-center randomized trial, patients who underwent first-time ERCP for choledocholithiasis were randomly assigned to three groups. The first group received 600 mg N-acetylcysteine 15 min prior to ERCP, and per-rectum administration of 50 mg indomethacin both prior to and after completion of the ERCP. The second group was administered only the 50 mg indomethacin per-rectum both prior to and after the ERCP. The third group was administered per-rectum 100 mg indomethacin only after the ERCP, representing the control group given the guideline-recommended regimen. The primary end-point was PEP prevention. RESULTS: Among the total 211 patients evaluated during the study, 186 fulfilled the inclusion criteria and completed the protocol. The percentages of patients who developed PEP in each of the three groups were not significantly different (χ 2 = 2.793, P = 0.247). Among the acute PEP cases, for all groups, 14 patients developed mild pancreatitis (77.77%) and 4 moderate. No severe cases of PEP occurred, and in all PEP cases the resolution was favorable. No adverse events related to the medications (digestive hemorrhage, rectal irritation, or allergies) occurred. CONCLUSION: The efficacies of split-dose indomethacin and combined administration (N-acetylcysteine with indomethacin) for preventing PEP were similar to that of the standard regimen.

New Insights into the Role of Trace Elements in IBD.

Micronutrient deficiencies are common in inflammatory bowel disease and have clinical impact, being both a sign of complicated disease and a cause of morbidity. The involved systemic inflammatory response is responsible for altering the concentration of a wide range of trace elements in the serum, including zinc and selenium. This review summarizes recent advances and evidence-based knowledge regarding the impact of selenium and zinc on oxidative stress and microbiota changes in IBD patients. Getting new insight into the impact of malnutrition, particularly on the micronutrients' impact on the development, composition, and metabolism of microbiota, as well as the influence of oxidative stress and the mucosal immune response, could help in implementing new management strategies for IBD patients, with focus on a more integrated approach.