Alimentary Pharmacology & Therapeutics最新文献

{"title":"Association between gut-derived endotoxins and porto-sinusoidal vascular disorder with portal hypertension","authors":"Stefania Gioia,&nbsp;Roberto Carnevale,&nbsp;Daniele Tavano,&nbsp;Diletta Overi,&nbsp;Lorenzo Ridola,&nbsp;Silvia Nardelli,&nbsp;Manuela Merli,&nbsp;Giulia d'Amati,&nbsp;Adriano Pellicelli,&nbsp;Vincenzo Cardinale,&nbsp;Valerio Giannelli,&nbsp;Andrea Baiocchini,&nbsp;Oliviero Riggio,&nbsp;Eugenio Gaudio,&nbsp;Guido Carpino","doi":"10.1111/apt.17727","DOIUrl":"10.1111/apt.17727","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Porto-sinusoidal vascular disorder (PSVD) is characterised by lesions involving portal veins and sinusoids in absence of cirrhosis with an unclear pathophysiology. However, its association with immunodeficiency, bowel disorders and abdominal bacterial infections supports the role of altered intestinal permeability and gut-derived endotoxins. The study aimed at assessing the association between serological markers of increased intestinal permeability, pro-aggregating/procoagulant state and liver injury in PSVD and portal hypertension.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Thirty-three patients with biopsy-proven PSVD and portal hypertension and 33 healthy subjects were submitted to a venous blood sampling for the measurement of zonulin and lipopolysaccharides (LPS) as markers of intestinal permeability, of s-Glycoprotein VI, sP-selectin, ADAMTS13 and von Willebrand factor (vWF), as markers of platelet aggregation and microvascular inflammation, factor VIII and F1 + 2 as markers of hypercoagulability. In 17 PSVD patients, histomorphological and immunohistochemical study on liver biopsies was performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with controls, PSVD patients had higher levels of LPS, zonulin, vWF, factor VIII and sP-selectin, F1 + 2. ADAMTS13 was reduced. Serum LPS correlated with zonulin, sP-selectin, FVIII and vWF. At histological analysis, PSVD specimens had increased LPS localisation, toll-like receptor-4(TLR4)-positive macrophages and platelet number compared with samples from healthy liver donors. TLR4+ macrophage number correlated with portal inflammation and fibrosis. Sinusoid dilation and capillarisation were observed. PSVD biopsies showed signs of biliary damage and reduced ductular reaction without alteration in Sox9+ cell population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>PSVD patients display an altered intestinal permeability and endotoxemia correlated to a pro-aggregating/procoagulant state; histologically, PSVD was associated with increased TLR4+ cell involvement and platelet clumps within sinusoids. Our study suggests that LPS-TLR4 pathway could contribute to the pathophysiological basis of PSVD with portal hypertension.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 11-12","pages":"1205-1216"},"PeriodicalIF":7.6,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microscopic colitis and risk of incident rheumatoid arthritis: A nationwide population-based matched cohort study","authors":"David Bergman,&nbsp;Bjorn Roelstraete,&nbsp;Jiangwei Sun,&nbsp;Fahim Ebrahimi,&nbsp;Johan Askling,&nbsp;Jonas F. Ludvigsson","doi":"10.1111/apt.17708","DOIUrl":"10.1111/apt.17708","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Microscopic colitis (MC) has been linked to several autoimmune conditions. Results from previous studies on the association with rheumatoid arthritis (RA) have been inconsistent.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To assess the risk of future RA in MC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a nationwide matched cohort study in Sweden of 8179 patients with biopsy-verified MC (diagnosed in 2007–2017), 36,400 matched reference individuals and 8202 siblings without MC, with follow-up until 2021. Information on MC was obtained from all of Sweden's regional pathology registers (<i>n</i> = 28) through the ESPRESSO cohort. Data on incident RA were collected from the National Patient Register. Using Cox regression, we calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During a median follow-up of 9.1 years (interquartile range = 6.7–11.7), 73 MC patients and 183 reference individuals from the general population were diagnosed with RA (99 vs. 55 events per 100,000 person-years), equivalent to one extra case of RA in 226 patients with MC followed for 10 years. These rates corresponded to an aHR of 1.83 (95% CI = 1.39–2.41). The aHR was highest during the first year of follow-up (2.31 [95% CI = 1.08–4.97]) and remained significantly elevated up to 5 years after MC diagnosis (aHR 2.16; 95% CI = 1.42–3.30). Compared to siblings, without MC, the aHR was 2.04 (95% CI = 1.18–3.56).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Patients with MC are at a nearly two-fold risk of developing RA compared to the general population. Knowledge of this increased risk may expedite evaluation for RA in patients with MC presenting with joint symptoms and/or arthralgia, thus preventing delay until RA diagnosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 10","pages":"1028-1040"},"PeriodicalIF":7.6,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17708","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAFLD fibrosis score: Using routine measures to identify advanced fibrosis in metabolic-associated fatty liver disease","authors":"Johnny T. K. Cheung,&nbsp;Xinrong Zhang,&nbsp;Grace Lai-Hung Wong,&nbsp;Terry Cheuk-Fung Yip,&nbsp;Huapeng Lin,&nbsp;Guanlin Li,&nbsp;Howard Ho-Wai Leung,&nbsp;Jimmy Che-To Lai,&nbsp;Sanjiv Mahadeva,&nbsp;Nik Raihan Nik Mustapha,&nbsp;Xiao-Dong Wang,&nbsp;Wen-Yue Liu,&nbsp;Vincent Wai-Sun Wong,&nbsp;Wah-Kheong Chan,&nbsp;Ming-Hua Zheng","doi":"10.1111/apt.17722","DOIUrl":"10.1111/apt.17722","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Early screening may prevent fibrosis progression in metabolic-associated fatty liver disease (MAFLD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>We developed and validated MAFLD fibrosis score (MFS) for identifying advanced fibrosis (≥F3) among MAFLD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This cross-sectional, multicentre study consecutively recruited MAFLD patients receiving tertiary care (Malaysia as training cohort [<i>n</i> = 276] and Hong Kong and Wenzhou as validation cohort [<i>n</i> = 431]). Patients completed liver biopsy, vibration-controlled transient elastography (VCTE), and clinical and laboratory assessment within 1 week. We used machine learning to select ‘highly important’ predictors of advanced fibrosis, followed by backward stepwise regression to construct MFS formula.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MFS was composed of seven variables: age, body mass index, international normalised ratio, aspartate aminotransferase, gamma-glutamyl transpeptidase, platelet count, and history of type 2 diabetes. MFS demonstrated an area under the receiver-operating characteristic curve of 0.848 [95% CI 0.800–898] and 0.823 [0.760–0.886] in training and validation cohorts, significantly higher than aminotransferase-to-platelet ratio index (0.684 [0.603–0.765], 0.663 [0.588–0.738]), Fibrosis-4 index (0.793 [0.735–0.854], 0.737 [0.660–0.814]), and non-alcoholic fatty liver disease fibrosis score (0.785 [0.731–0.844], 0.750 [0.674–0.827]) (DeLong's test <i>p</i> &lt; 0.05). MFS could include 92.3% of patients using dual cut-offs of 14 and 15, with a correct prediction rate of 90.4%, resulting in a larger number of patients with correct diagnosis compared to other scores. A two-step MFS-VCTE screening algorithm demonstrated positive and negative predictive values and overall diagnostic accuracy of 93.4%, 89.5%, and 93.2%, respectively, with only 4.0% of patients classified into grey zone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>MFS outperforms conventional non-invasive scores in predicting advanced fibrosis, contributing to screening in MAFLD patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 11-12","pages":"1194-1204"},"PeriodicalIF":7.6,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abdominal pain in patients with inflammatory bowel disease in remission: A prospective study on contributing factors","authors":"L. M. Janssen,&nbsp;A. Rezazadeh Ardabili,&nbsp;M. J. L. Romberg-Camps,&nbsp;B. Winkens,&nbsp;R. J. van den Broek,&nbsp;J. Hulst,&nbsp;H. J. A. Verwijs,&nbsp;D. Keszthelyi,&nbsp;D. M. A. E. Jonkers,&nbsp;A. A. van Bodegraven,&nbsp;M. J. Pierik,&nbsp;Z. Mujagic","doi":"10.1111/apt.17718","DOIUrl":"10.1111/apt.17718","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Abdominal pain is highly prevalent in patients with inflammatory bowel disease (IBD) in remission, but the aetiology is incompletely understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To investigate the association of clinical, lifestyle and psychosocial factors with abdominal pain in patients with IBD in remission.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a prospective multicentre study enrolling consecutive patients with IBD. Data were collected between 1 January 2020 and 1 July 2021, using myIBDcoach, an established remote monitoring platform for IBD. Chronic abdominal pain in IBD in remission (IBD<i>remission</i>Pain+) was defined as abdominal pain score ≥3 (0–10 NRS) on ≥1/3 of all assessments, combined with faecal calprotectin &lt;150 μg/g in 90 days around periodic assessments. Disease activity, lifestyle and psychosocial factors were assessed every 1–3 months during 18 months. Using linear mixed models, the association of these factors with abdominal pain over time was analysed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 559 patients, of whom 429 (76.7%) remained in biochemical remission. Of these, 198 (46.2%) fulfilled the criteria for chronic abdominal pain. IBD<i>remission</i>Pain+ patients were characterised by female sex, younger age, higher BMI, and shorter disease duration. They reported more often or higher levels of stress, fatigue, depressive and anxiety symptoms, and life events (all <i>p</i> &lt; 0.001). In the multivariable analysis, sex, disease entity, fatigue, depressive symptoms and life events were associated with abdominal pain over time (all <i>p</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In this cohort of patients with IBD in remission, abdominal pain was common and associated with psychosocial factors. A more holistic treatment approach for patients with IBD suffering from abdominal pain may improve quality of care and subjective wellbeing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 10","pages":"1041-1051"},"PeriodicalIF":7.6,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17718","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41090276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy-confirmed nonalcoholic steatohepatitis","authors":"Naim Alkhouri,&nbsp;Donald Lazas,&nbsp;Rohit Loomba,&nbsp;Juan P. Frias,&nbsp;Shibao Feng,&nbsp;Leo Tseng,&nbsp;Kemal Balic,&nbsp;Germaine D. Agollah,&nbsp;Tinna Kwan,&nbsp;Janani S. Iyer,&nbsp;Linda Morrow,&nbsp;Hank Mansbach,&nbsp;Maya Margalit,&nbsp;Stephen A. Harrison","doi":"10.1111/apt.17709","DOIUrl":"10.1111/apt.17709","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy-confirmed NASH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This proof-of-concept, open-label, single-cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21–75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2-point improvement in NAFLD activity score with ≥1-point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least-squares mean relative change from baseline in MRI-PDFF was −64.7% (95% CI: −71.7, −57.7; <i>p</i> &lt; 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH. ClinicalTrials.gov: NCT04048135.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 10","pages":"1005-1015"},"PeriodicalIF":7.6,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10286969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated safety analysis of filgotinib for ulcerative colitis: Results from SELECTION and SELECTIONLTE","authors":"Stefan Schreiber,&nbsp;Gerhard Rogler,&nbsp;Mamoru Watanabe,&nbsp;Séverine Vermeire,&nbsp;Christian Maaser,&nbsp;Silvio Danese,&nbsp;Margaux Faes,&nbsp;Paul Van Hoek,&nbsp;Jeremy Hsieh,&nbsp;Ulrik Moerch,&nbsp;Yan Zhou,&nbsp;Angela de Haas,&nbsp;Christine Rudolph,&nbsp;Alessandra Oortwijn,&nbsp;Edward V. Loftus Jr","doi":"10.1111/apt.17674","DOIUrl":"10.1111/apt.17674","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long-term extension study SELECTIONLTE (NCT02914535).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11-week SELECTION induction study, the 47-week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure-adjusted incidence rates (EAIRs) per 100 censored patient-years of exposure with 95% confidence intervals were reported for treatment-emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This interim analysis included 1348 patients representing 3326.2 patient-years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic-experienced than biologic-naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> ClinicalTrials.gov Identifiers (NCT numbers)</h3>\u0000 \u0000 <p>NCT02914522, NCT02914535.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 9","pages":"874-887"},"PeriodicalIF":7.6,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17674","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10279482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver disease progression in patients with alpha-1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease","authors":"Tiffany Wu,&nbsp;May Hagiwara,&nbsp;Esteban Gnass,&nbsp;Hannah Barman,&nbsp;David Sasson,&nbsp;William Treem,&nbsp;Kaili Ren,&nbsp;Ed G. Marins,&nbsp;Chitra Karki,&nbsp;Harmeet Malhi","doi":"10.1111/apt.17715","DOIUrl":"10.1111/apt.17715","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in <i>SERPINA1</i>, which encodes alpha-1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To characterise patients with AATD Pi*ZZ and liver disease (AATD-LD-Pi*ZZ) with or without lung disease and describe liver disease-related clinical events longitudinally.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000–September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0–F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow-up. Clinical events associated with liver disease progression were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AATD-LD-Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease-related clinical events (8.5 years and not reached, respectively). AATD-LD-Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 10","pages":"1075-1085"},"PeriodicalIF":7.6,"publicationDate":"2023-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17715","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10285998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Less is more for colorectal cancer diagnosis – FIT leads the way","authors":"Robert P. H. Logan,&nbsp;William Hamilton","doi":"10.1111/apt.17662","DOIUrl":"https://doi.org/10.1111/apt.17662","url":null,"abstract":"&lt;p&gt;Symptoms have traditionally been the mainstay of clinical diagnosis and were the basis of the original NICE NG12 GP referral guidelines for patients at risk of colorectal cancer (CRC).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Attempts to increase earlier diagnosis of CRC by lowering referral thresholds and broadening referral criteria created further demand for colonoscopy. Despite the expansion in eligibility for urgent testing, many cancers were still identified in routinely referred patients.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The use of Faecal immunochemical testing (FIT), introduced in the UK in 2017, was transformed by the COVID-19 pandemic. Colonoscopy came to a halt, and the need to identify patients at highest risk of CRC was facilitated by diagnostic accuracy studies of FIT, with preliminary data showing that CRC was rarely found in patients with FIT values below 10 μg/g of faeces. The emergency pandemic guidance from NHS-England provided alternative management pathways for most patients and has subsequently been supported by a large systematic review,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and most recently by draft NICE guidance.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;However, these studies were too small to consider other potentially relevant factors such as age, gender, and the presence of anaemia (iron deficient or otherwise) despite clear epidemiological evidence linking CRC to these risk factors.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Crooks &lt;i&gt;et al&lt;/i&gt; tackled this issue and posited a more sophisticated pathway, including age (in 15-year bands) and haemoglobin values.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The study, from a cohort of over 33,000 patients with FIT and haemoglobin results, introduced these two variables by identifying adjusted FIT thresholds above which the risk of cancer was 3%. In those with a normal haemoglobin and a FIT level between 20 and 40 μg/g faeces, only those aged over 85 years had a risk of cancer exceeding 3%. Not surprisingly, anaemia increased the risk; anaemic patients with a FIT over 20 μg/g faeces had &gt;3% chance of CRC except in the small group aged under 40 years.&lt;/p&gt;&lt;p&gt;This study has raised the possibility of using evidenced differential FIT thresholds for selecting those for definitive testing, which could be sophisticated - colonoscopy for those at highest risk, CT colonography (or, perhaps, colon capsule) for intermediate risk, and safety-netting in primary care, perhaps with repeat FIT for those at lowest risk.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Will this be implemented? First, since this is only one study, replication is essential, but may not be simple.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; An older Spanish equation failed replication, although it was a small study.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; Other factors may be relevant, such as platelet count and gender, although it is unlikely that these will add much predictive power. Adoption will also have to resolve the tension between the current simple guidance, with a single threshold of 10 μg/g, which is easy to impl","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 7","pages":"725-726"},"PeriodicalIF":7.6,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6763147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter: Safety after cessation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B infection—Authors' reply","authors":"Yao-Chun Hsu,&nbsp;Mindie H. Nguyen,&nbsp;Chun-Ying Wu","doi":"10.1111/apt.17681","DOIUrl":"https://doi.org/10.1111/apt.17681","url":null,"abstract":"&lt;p&gt;We thank Liu &lt;i&gt;et al&lt;/i&gt; for their interest in our study. We agree that pre-treatment HBeAg status could influence the risk of severe hepatitis flares after withdrawal of nucleos(t)ide analogue (NUCs). However, the limited number of events restricted our ability to explore risk predictors in the eligible sub-cohort, defined by available data to document negative HBeAg and undetectable hepatitis B virus DNA with a period of treatment consolidation prior to treatment cessation. Nonetheless, our data highlight the insufficiency of current stopping rules in safeguarding patients from severe withdrawal flares, irrespective of their pre-treatment HBeAg status. As Liu &lt;i&gt;et al&lt;/i&gt; reported, both HBeAg-positive and -negative patients meeting the Asian-Pacific criteria for NUC discontinuation could suffer from liver failure and even death due to severe withdrawal flares.&lt;/p&gt;&lt;p&gt;We also agree that tenofovir disoproxil fumarate (TDF), when compared to entecavir (ETV), was associated with a higher risk of clinical relapse following treatment cessation.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, we did not find an association between the antiviral regimen and hepatic decompensation from withdrawal flares in our study.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; If Liu et al. had reviewed our article more thoroughly, they certainly would have noticed in the appendix that this factor was included in our multivariable model.&lt;/p&gt;&lt;p&gt;Our findings align with existing literature. For instance, analyses of the international RETRACT-B consortium showed that, while TDF was linked to an earlier occurrence of virological relapse and a higher rate of clinical relapse,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; it did not differ from ETV in the incidence of hepatic decompensation.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This was corroborated by a recent hospital-based study, in which TDF conferred a higher rate of relapse and an earlier occurrence in HBeAg-positive patients but all of five patients who developed hepatic decompensation were withdrawing from ETV instead of TDF (5/96 vs. 0/70; &lt;i&gt;p&lt;/i&gt; = 0.074).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; In our view, the discrepancy could be attributed to the timing of re-treatment as an earlier relapse may lead to an earlier resumption of antiviral treatment.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Contrary to the suggestion by Liu &lt;i&gt;et al&lt;/i&gt;, our approach, based on the national healthcare database in Taiwan, is less susceptible to attrition bias. Given the universal coverage of Taiwan's national health insurance,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; our outcome measurements did not rely on follow-up at a specific hospital. Moreover, we reported the duration of treatment consolidation in the eligible sub-cohort (section 3.4). Our analysis on post-treatment monitoring, with details available in the appendix, indicated that most serious outcomes did not result from poor adherence to medical attention.&lt;/p&gt;&lt;p&gt;We respectfully disagree with the assertion that our data inflated the risk of off-NUC hepatic decompensation. This","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 7","pages":"733-734"},"PeriodicalIF":7.6,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6895475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter: Safety after cessation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B infection","authors":"Yen-Chun Liu,&nbsp;Wen-Juei Jeng,&nbsp;Rong-Nan Chien","doi":"10.1111/apt.17657","DOIUrl":"https://doi.org/10.1111/apt.17657","url":null,"abstract":"&lt;p&gt;We read with great concern of the study by Hsu et al&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; on severe hepatitis flare with decompensation after cessation of nucleos(t)ide analogue (NUC) based on a large database of patients with chronic hepatitis B (CHB) infection in Taiwan. The study showed 4-year cumulative incidence of off-therapy hepatic decompensation and mortality/liver transplantation 1.8% and 0.7%, respectively; the 4-year incidence of hepatic decompensation decreased to 1.3% in patients without evidence of cirrhosis and 1.1% in those adhering to a standardised stopping rule. In addition to the inherent problems of an administrative database, several points deserve clarification and further discussion.&lt;/p&gt;&lt;p&gt;First, HBeAg-positive and negative CHB are different disease entities with different risks of off-therapy hepatic decompensation. In our off-NUC cohort including 295 HBeAg-positive and 1234 HBeAg-negative patients, the cumulative decompensation incidence was higher in HBeAg-positive than in HBeAg-negative patients: 1-year 2.4% vs. 0.97%, 2-year 2.4% vs. 1.2%.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Among patients without cirrhosis in our off-NUC cohort, the 2-year cumulative incidence of decompensation was 0.8% and 0.1%, respectively, but 8-fold higher in HBeAg-positive patients. Given such differences, HBeAg-positive and HBeAg-negative patients need to be addressed separately. Second, off-therapy flares in patients stopping tenofovir disoproxil fumarate (TDF) occur more frequently and are more severe than off-entecavir flares, and TDF use and cirrhosis are independent predictors of severe flare and hepatic decompensation.&lt;span&gt;&lt;sup&gt;2, 4&lt;/sup&gt;&lt;/span&gt; This study did not stratify the decompensation risk by NUC types and did not include the NUC types into the regression analysis. Third, most patients in this study lacked the information of consolidation duration, and the proportion of self-discontinuation of NUC or loss-to-follow-up, all of which are crucial factors associated with off-therapy severe flare.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The 5-year cumulative incidence of on-treatment loss-to-follow-up may be up to 11%.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Patients who stop NUC by themselves or who are lost to follow-up may have similar risk of hepatitis flare but higher risk of decompensation or liver-related mortality because they would be not properly monitored and treated in time.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Of note, the rates of decompensation in off-NUC studies are not higher than those from long-term NUC treatment, even in patients with cirrhosis.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Safety after stopping NUC is of paramount importance. However, this database study may have provided inflated data of off-NUC hepatic decompensation as compared with those from hospital-based studies. This may highlight the importance of proper off-NUC monitoring and education of patients.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Yen-Chun Liu:&lt;/b&gt; Formal analysis (lead); writing – original draft (lead). &lt;b&gt;Wen-Juei Jeng:&lt;/","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"58 7","pages":"731-732"},"PeriodicalIF":7.6,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.17657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6894208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}