Neutrophil Extracellular Traps Contribute to Liver Damage and Increase Defective Low-Density Neutrophils in Alcohol-Associated Hepatitis

Neutrophils contribute to liver damage through increased NET formation which increases defective LDNs in AH. Alcohol induces phenotypic changes in neutrophils; HDNs are activated whereas LDNs are defective.

source: J Hepatology

Summary

[Posted 19/Jan/2023]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Neutrophils contribute to liver damage through increased NET formation which increases defective LDNs in AH. Alcohol induces phenotypic changes in neutrophils; HDNs are activated whereas LDNs are defective. Findings provide mechanistic insights that could guide the development of therapeutic interventions for AH.

BACKGROUND: In alcohol-associated hepatitis (AH), inflammation and neutrophil counts correlate with poor clinical outcomes. Here, we investigated how neutrophils contribute to liver damage in AH. Authors isolated blood neutrophils from individuals with AH to examine neutrophil extracellular traps (NETs) and performed RNA sequencing to explore their unique characteristics.

DETAILS: A significant increase was observed in NET production in AH. Also observed a unique low-density neutrophil (LDN) population in individuals with AH and alcohol-fed mice that was not present in healthy controls. Transcriptome analysis of peripheral LDNs and high-density neutrophils (HDNs) from individuals with AH revealed that LDNs exhibit a functionally exhausted phenotype, while HDNs are activated. Indeed, AH HDNs exhibited increased resting reactive oxygen species (ROS) production and produced more ROS upon lipopolysaccharide stimulation than control HDNs, whereas AH LDNs failed to respond to lipopolysaccharide. We show that LDNs are generated from HDNs after alcohol-induced NET release in vitro, and this LDN subset has decreased functionality, including reduced phagocytic capacity. Moreover, LDNs showed reduced homing capacity and clearance by macrophage efferocytosis; therefore, dysfunctional neutrophils could remain in the circulation and liver. Depletion of both HDNs and LDNs in vivo prevented alcohol-induced NET production and liver damage in mice. Granulocyte-colony stimulating factor treatment also ameliorated alcohol-induced liver injury in mice.

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Source: Cho, Y., Bukong, T. N., Tornai, D., et al. (2022). Neutrophil Extracellular Traps Contribute to Liver Damage and Increase Defective Low-Density Neutrophils in Alcohol-Associated Hepatitis. J Hepatology. Published: December, 2022. DOI: 10.1016/j.jhep.2022.08.029.



Clinical Prediction Models for Pancreatic Cancer in General and At-Risk Populations

Identifying high-risk individuals using a risk prediction model could be a crucial first stage of screening pathways to improve the early detection of pancreatic cancer.

source: Am J Gastro.

Summary

A Systematic Review

[Posted 30/Jan/2023]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Many clinical risk prediction models for pancreatic cancer had been developed for different target populations. Although low risk-of-bias studies were identified, these require external validation and implementation studies to ensure that these will benefit clinical decision making.

BACKGROUND: Identifying high-risk individuals using a risk prediction model could be a crucial first stage of screening pathways to improve the early detection of pancreatic cancer. A systematic review was conducted to critically evaluate the published primary literature on the development or validation of clinical risk prediction models for pancreatic cancer risk.

DETAILS: MEDLINE, Embase, and Web of Science were searched for relevant articles from the inception of each database up to November 2021. Study selection and data extraction were conducted by 2 independent reviewers. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was applied to assess risk of bias. In total, 33 studies were included, describing 38 risk prediction models. Excluding studies with an overlapping population, this study consist of 15,848,100 participants, of which 58,313 were diagnosed with pancreatic cancer. Eight studies externally validated their model, and 13 performed internal validation. The studies described risk prediction models for pancreatic cancer in the general population (n = 14), patients with diabetes (n = 8), and individuals with gastrointestinal (and other) symptoms (symptoms included abdominal pain, unexplained weight loss, jaundice, and change in bowel habits and indigestion; n = 11). The commonly used clinical risk factors in the model were cigarette smoking (n = 27), age (n = 25), diabetes history (n = 22), chronic pancreatitis (n = 18), and body mass index (n = 14). In the 25 studies that assessed model performance, C-statistics ranged from 0.61 to 0.98. Of the 33 studies included, 6 were rated as being at a low risk of bias based on PROBAST.

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Source: Santos, R., Coleman, H. G., Cairnduff, V., et al. (2022). Clinical Prediction Models for Pancreatic Cancer in General and At-Risk Populations: A Systematic Review. American Journal of Gastroenterology. 2023; 118(1): 26-40. Published: January, 2023. DOI: 10.14309/ajg.0000000000002022.



A Novel Unconventional T Cell Population Enriched In Crohn's Disease

Identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population.

source: Gut

Summary

[Posted 23/Nov/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.

BACKGROUND: One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls.

DETAILS: Bulk TCR repertoire profiling of both the TCR alpha and beta chains was performed using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. It was further characterised specific T cell clonotypes via single-cell RNAseq. Identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn's disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs.

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Source: Rosati, E., Rios Martini G., Pogorelyy, M. V., et al. (2022). A Novel Unconventional T Cell Population Enriched In Crohn's Disease. Gut. 2022; 71(11): 2194-2204. Published: November, 2022. DOI: XXXXXXXX.



Effectiveness and Safety of Tofacitinib for Ulcerative Colitis

While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation.

source: J Clin Gastro

Summary

Systematic Review and Meta-analysis

[Posted 10/Nov/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation. Rate of clinical response after tofacitinb induction was similar in biologic naive and biologic experienced patients.

BACKGROUND: The objective of our systematic review and meta-analysis was to evaluate the effectiveness and safety of tofacitinib in the treatment of moderate-severe ulcerative colitis (UC).

DETAILS: Authors searched Medline, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on tofacitinib use in UC. Primary outcome assessed was remission. Secondary outcomes included clinical response, steroid free remission, and adverse events (AEs). A total of 26 studies were included. The rates of remission were 29.81% [95% confidence interval (CI): 22.37%-37.25%, I2: 90%] at week 8, 32.27% (95% CI: 27.67%-36.88%, I2: 42%) at 6 months and 38.03% (95% CI: 33.59%-42.48%, I2: 0%) at 1-year. Clinical response rates were 59.41% (95% CI: 55.03%-63.94%, I2: 61%) at week 8, 48.99% (95% CI: 36.92%-61.06%, I2: 91%) at 6 months and 50.87% (95% CI: 42.16%-59.58%, I2: 67%) at 1-year. Odds ratio of clinical response at week 8 in biologic naive versus biologic experienced patients was 1.59 (95% CI: 0.54-4.63). Pooled incidence rate for serious infections, major adverse cardiovascular events, and nonmelanotic squamous cell malignancies across all doses was 4.41 per 100-patient years (PYs) (95% CI: 2.32-8.38 per 100-PY, I2: 78%), 0.91 per 100-PY (95% CI: 0.43-1.93 per 100-PY, I2: 37%) and 0.91 per 100-PY (95% CI: 0.61-1.34 per 100-PY, I2: 0%), respectively. Higher dose was associated with an increased frequency of AEs.

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Source: Taneja, V., El-Dallal, M., Haq, Z., et al. (2022). Effectiveness and Safety of Tofacitinib for Ulcerative Colitis: Systematic Review and Meta-analysis. J Clin Gastro. 2022; 56(10): e323-e333. Published: November/December, 2022. DOI: 10.1097/MCG.0000000000001608.



An Endoscopic and Histologic Study on Healing of Radiofrequency Ablation Wounds in Patients With Barrett's Esophagus

RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands.

source: Am J Gastro.

Summary

[Posted 26/Oct/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands in which esophageal submucosal gland duct cells seem to redifferentiate into the squamous progenitors that fuel squamous re-epithelialization. SSIM can be found in most patients during the healing process. We speculate that this SSIM might underlie Barrett's recurrences after apparently successful eradication.

BACKGROUND: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) inflicts a wound spanning 3 epithelial types (stratified squamous, Barrett's metaplasia, gastric epithelium), yet the esophageal injury heals almost completely with squamous epithelium. Knowledge of how this unique wound heals might elucidate mechanisms underlying esophageal metaplasia. We aimed to prospectively and systematically characterize the early endoscopic and histologic features of RFA wound healing.

DETAILS: Patients with nondysplastic BE had endoscopy with systematic esophageal photographic mapping, biopsy, and volumetric laser endomicroscopy performed before and at 1, 2, and 4 weeks after RFA. Seven patients (6 men; mean age 56.1 ± 10.9 years) completed this study. Squamous re-epithelialization of RFA wounds did not only progress exclusively through squamous cells extending from the proximal wound edge but also progressed through islands of squamous epithelium sprouting throughout the ablated segment. Volumetric laser endomicroscopy revealed significant post-RFA increases in subepithelial glandular structures associated with the squamous islands. In 2 patients, biopsies of such islands revealed newly forming squamous epithelium contiguous with immature-appearing squamous cells arising from esophageal submucosal gland ducts. Subsquamous intestinal metaplasia (SSIM) was found in biopsies at 2 and/or 4 weeks after RFA in 6 of 7 patients.

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Source: Konda, V., Souza, R. F., Dunbar, K. B. et al. (2022). An Endoscopic and Histologic Study on Healing of Radiofrequency Ablation Wounds in Patients With Barrett's Esophagus. Am J Gastro.. 2022; 17(10): 1583-1592. Published: October, 2022. DOI: 10.14309/ajg.0000000000001940.



Association of Celiac Serology Normalization With the Risk of Hypothyroidism

During the study it was reported that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population.

source: Am J Gastro.

Summary

A Cohort Study

[Posted 27/Sep/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: In this retrospective, age-stratified analysis, it was reported that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population. Prospective cohorts are needed to validate our findings.

BACKGROUND: During the study whether persistent-positive celiac serology is associated with the risk of hypothyroidism was evaluated.

DETAILS: Extracted a cohort of subjects aged 1-80 years with a positive IgA anti-tissue transglutaminase between January 1, 2008, and December 31, 2012, and a repeat anti-tissue transglutaminase test within 6-36 months from a large population-based electronic medical record database. Based on serology tests, categorized the pediatric (age <21 years) and adult cohorts into normalized or persistent-positive serology groups. All subjects were followed up for incident diagnosis of hypothyroidism from the last serology date up to December 31, 2017. Hazard ratio (HR) along 95% confidence intervals (CIs) were prepared to evaluate the association of celiac serology group with a diagnosis of hypothyroidism, crude, and adjusted for age, sex, and diagnosis of type 1 diabetes mellitus. Among the pediatric cohort (n = 2,687), during a median follow-up of 64 months (interquartile range 48-80), 2.3% (16/681) of the persistent-positive serology group and 1.0% (20/2,006) of the normalized serology group developed hypothyroidism (HR 2.07 [95% CI 1.07-4.44], adjHR 1.77 [95% CI 0.91-3.46]). The rate among the pediatric cohort with an established diagnosis of celiac disease was 3.4% (10/486) vs 1.0% (5/481), HR 2.83 (0.96-8.32). In the adult cohort (n = 1,286), 4.5% (20/442) of the persistent-positive group and 3.9% (33/811) of the normalized serology group developed hypothyroidism (HR 1.13 [95% CI 0.65-1.97]).

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Source: Golan, M. A., Feldman, B., Ollech, J. E., et al. (2022). Association of Celiac Serology Normalization With the Risk of Hypothyroidism: A Cohort Study. American Journal of Gastroenterology. 2022; 117(9): 1428-1436, 2022Published: September 2022. DOI: 10.14309/ajg.0000000000001872.



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