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The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD. Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.

Objectives To prospectively evaluate a 3D-multiecho-Dixon sequence with inline calculation of proton density fat fraction (PDFF) and R2* (qDixon), and an improved version of it (qDixon-WIP), for the MR-quantification of hepatic iron in a clinical setting. Methods Patients with increased serum ferritin underwent 1.5-T MRI of the liver for the evaluation of hepatic iron overload. The imaging protocol for R2* quantification included as follows: (1) a validated, 2D multigradient-echo sequence (initial TE 0.99 ms, R2*-ME-GRE), (2) a 3D-multiecho-Dixon sequence with inline calculation of PDFF and R2* (initial TE 2.38 ms, R2*-qDixon), and optionally (3) a prototype (works-in-progress, WIP) version of the latter (initial TE 1.04 ms, R2*-qDixon-WIP) with improved water/fat separation and noise-corrected parameter fitting. For all sequences, three manually co-registered regions of interest (ROIs) were placed in the liver. R2* values were compared and linear regression analysis and Bland-Altman plots calculated. Results Forty-six out of 415 patients showed fat-water (F/W) swap with qDixon and were excluded. A total of 369 patients (mean age 52 years) were included; in 203/369, the optional qDixon-WIP was acquired, which showed no F/W swaps. A strong correlation was found between R2*-ME-GRE and R2*-qDixon ( r 2 = 0.92, p < 0.001) with Bland-Altman revealing a mean difference of − 3.82 1/s (SD = 21.26 1/s). Correlation between R2*-GRE-ME and R2*-qDixon-WIP was r 2 = 0.95 ( p < 0.001) with Bland-Altman showing a mean difference of − 0.125 1/s (SD = 30.667 1/s). Conclusions The 3D-multiecho-Dixon sequence is a reliable tool to quantify hepatic iron. Results are comparable with established relaxometry methods. Improvements to the original implementation eliminate occasional F/W swaps and limitations regarding maximum R2* values. Key Points • The 3D-multiecho-Dixon sequence for 1.5 T is a reliable tool to quantify hepatic iron. • Results of the 3D-multiecho-Dixon sequence are comparable with established relaxometry methods. • An improved version of the 3D-multiecho-Dixon sequence eliminates minor drawbacks.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.This Consensus Statement discusses the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction. The authors propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, highlight research gaps and provide suggestions for the design and outcome measures for future studies.

Severe alcoholic hepatitis (sAH) confers substantial mortality, but the disease course is difficult to predict. As iron parameters are attractive outcome predictors in other liver diseases, we tested their prognostic ability in sAH. Serum ferritin, transferrin, iron, transferrin saturation, nontransferrin-bound iron, soluble transferrin receptor, and hepcidin were measured in 828 patients with sAH recruited prospectively through the STOPAH trial. The cohort was randomly divided into exploratory (n = 200) and validation sets (n = 628). Patients with sAH had diminished serum transferrin but increased transferrin saturation. Among iron parameters, baseline transferrin was the best predictor of 28-day (area under the receiver operated characteristic 0.72 [95% confidence interval 0.67-0.78]) and 90-day survival (area under the receiver operated characteristic 0.65 [0.61-0.70]). Transferrin's predictive ability was comparable with the composite scores, namely model of end-stage liver disease, Glasgow alcoholic hepatitis score, and discriminant function, and was independently associated with survival in multivariable analysis. These results were confirmed in a validation cohort. Transferrin did not correlate with markers of liver synthesis nor with non-transferrin-bound iron or soluble transferrin receptor (as markers of excess unbound iron and functional iron deficiency, respectively). In patients with sAH, serum transferrin predicts mortality with a performance comparable with commonly used composite scoring systems. Hence, this routinely available parameter might be a useful marker alone or as a component of prognostic models.

Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM. To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort. Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included. The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM-OR = 20.8; 95% CI, 2.6-166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation. Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

The single nucleotide polymorphism rs12979860 is associated with the production of IFNλ4, a type III interferon, which offers protection from viral infection via its proinflammatory properties. We investigated if a genetically determined increase in IFNλ4 affects disease progression in SARS-CoV-2. This prospective, single-center study involved critically ill SARS-CoV-2 patients admitted to the intensive care unit. We performed genotyping for rs12979860 and analyzed daily laboratory data. Genotype frequencies were compared with an external validation cohort. Critically ill individuals with COVID-19 (n = 184; 29.3% women) were included. Median age was 63 years. The TT genotype was present in 11%, CT in 48% and CC in 41%. At baseline, CRP, ferritin, transferrin and neopterin did not differ significantly between groups. Longitudinal analysis revealed significant genotype-dependent differences in CRP, ferritin and neopterin with the highest peak in TT patients after 10–15 days. A higher need for renal replacement therapy (31.6% vs. 11.7%, p  = 0.044) and mechanical ventilation (22 days vs. 15 days, p  = 0.018) was observed in the TT group. The SNP rs12979860 near IFNL4 is associated with distinct inflammatory trajectories in critically ill COVID-19 patients. Genetic determinants of the immune response influence the severity of inflammation and clinical outcomes in severe COVID-19.

Background Three patients with portal hypertension and gastrointestinal bleeding due to non-cirrhotic portal vein thrombosis were treated with portal venous recanalization transjugular intrahepatic portosystemic shunt (PVR-TIPS) via a trans-splenic access. Main body A “bottoms-up” retrograde puncture of the right hepatic vein was performed using a re-entry catheter to gain access to the right hepatic vein. In all patients a successful retrograde puncture of the right hepatic vein was achieved, thereby restoring the splenoportal tract. Conclusion Our cases present an alternative approach to treat chronic portal vein thrombosis expanding the possibilities of the PVR-TIPS procedure.

Background Endoscopic retrograde cholangiography (ERC) possesses a translocation risk of microbes to the biliary system. We studied bile contamination during ERC and its impact on patients’ outcome in a real-life-situation. Methods Ninety-nine ERCs were analyzed and microbial samples were taken from the throat before and from bile during ERC and from irrigation fluid of the duodenoscope before and after ERC. Results 91.2% of cholangitis patients had detectable microbes in the bile (sensitivity 91%), but the same was true for 86.2% in the non-cholangitis group. Bacteroides fragilis ( p =0.015) was significantly associated with cholangitis. In 41.7% of ERCs with contaminated endoscopes these microbes were found in the bile after the procedure. Analysis of duodenoscopes’ irrigation liquid after ERC matched the microbial bile analysis of these patients in 78.8%. Identical microbial species were in throat and in bile samples of the same ERC in 33% of all cases and in 45% in the non-cholangitis group. Transmission of microbes to the biliary tract did not result in more frequent cholangitis, longer hospital stays, or worse outcome. Conclusions During ERC bile samples are regularly contaminated with microbes of the oral cavity but it did not affect clinical outcome.

Andreas Janecke and colleagues identify mutations in MYO5B , encoding the type Vb myosin motor protein, in individuals with microvillus inclusion disease, implicating myosin Vb as a key regulator of epithelial cell polarity. Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B , encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID.