A prospective study on the prevalence of MASLD in people with type-2 diabetes in the community. Cost effectiveness of screening strategies

Background and Aims: As screening for the liver disease and risk-stratification pathways are not established in patients with type-2 diabetes mellitus (T2DM), we evaluated the diagnostic performance and the cost-utility of different screening strategies for MASLD in the community.// Methods: Consecutive patients with T2DM from primary care underwent screening for liver diseases, ultrasound, ELF score and transient elastography (TE). Five strategies were compared to the standard of care: ultrasound plus abnormal liver function tests (LFTs), Fibrosis score-4 (FIB-4), NAFLD fibrosis score, Enhanced liver fibrosis test (ELF) and TE. Standard of care was defined as abnormal LFTs prompting referral to hospital. A Markov model was built based on the fibrosis stage, defined by TE. We generated the cost per quality-adjusted life year (QALY) gained and calculated the incremental cost-effectiveness ratio (ICER) over a lifetime horizon.// Results: Of 300 patients, 287 were included: 64% (186) had MASLD and 10% (28) had other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287) and 3% (8/287), respectively. Among those with significant fibrosis classified by LSM≥8.1 kPa, false negatives were 54% from ELF and 38% from FIB-4. On multivariate analysis, waist circumference, BMI, AST levels and education rank were independent predictors of significant and advanced fibrosis. All the screening strategies were associated with QALY gains, with TE (148.73 years) having the most substantial gains, followed by FIB-4 (134.07 years), ELF (131.68 years) and NAFLD fibrosis score (121.25 years). In the cost-utility analysis, ICER was £2480/QALY for TE, £2541.24/QALY for ELF and £2059.98/QALY for FIB-4.// Conclusion: Screening for MASLD in the diabetic population in primary care is cost-effective and should become part of a holistic assessment. However, traditional screening strategies, including FIB-4 and ELF, underestimate the presence of significant liver disease in this setting

Letter: liver disease and COVID-19 - not the perfect storm

This article is linked to Garrido et al papers. To view these articles, visit https://doi.org/10.1111/apt.15813 and https://doi.org/10.1111/apt.15886

Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients

Background &amp; Aims: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. Methods: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). Results: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p &lt;0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. Conclusion: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease. Impact and implications: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease.</p

Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients

Background &amp; Aims: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. Methods: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). Results: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p &lt;0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. Conclusion: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Achaiki Iatriki : official publication of the medical society of western Greece and Peloponnesus

In the current issue, the editorial by Cauchi et al. argues for eco-friendly measures in endoscopy and emphasies the role of healthcare providers in reducing waste. The editorial adeptly employs the three Rs (Reduce, Reuse, Recycle) framework to tackle waste management, offering practical solutions. The editorial by Milionis et al. focuses on the reverse cascade screening for paediatric familial hypercholesterolaemia (FH), which is an upcoming tool for public health. Advantages, practices, and challenges regarding FH are thoroughly discussed. Lastly, the editorial by Fousekis et al. presents the main aspects of a chronic immune-mediated cutaneous disease, dermatitis herpetiformis (DH), which constitutes an extraintestinal manifestation of celiac disease, including its diagnosis, pathogenesis, and management. Moreover, this issue includes three review articles. The review article by Krontira et al. discusses the evolving data on the epidemiology, diagnostic approach and appropriate management of foreign body and caustic substance ingestion, based on updated guidelines published by gastroenterological and endoscopic societies. The review by Halliasos et al. provides data on the clinical presentation, diagnosis, and management of metastatic acute spinal cord compression, focusing on the importance of a multidisciplinary team approach, including spine surgeons, radiation oncologists, medical oncologists, palliative care clinicians, physiotherapists, and psychologists. Lastly, the review by Schinas et al. outlines the potential of immune modulation in the treatment of infections and the need for individualised approaches in the modern world of personalised medicine by examining some of the key strategies and immune-based therapies being developed to combat infectious diseases.peer-reviewe

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (&lt;380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

Crosstalk between colonic epithelial cells and T lymphocytes: the role of chemokines

Human colonic epithelial cells express Th1-associated chemoattractants, yet little is known about the production of Th2-associated chemoattractants. Furthermore, T-lymphocyte migration is implicated in the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). CXC chemokines MIG, IP-10, and I-TAC act by binding to the CXCR3A or the splice variant CXCR3B receptor on Th1-lymphocytes. On the other hand, CC chemokines, CCL11/Eotaxin-1, CCL24/Eotaxin-2, and CCL26/Eotaxin-3 are known to attract CCR3-expressing, Th2-polarized lymphocytes. We investigated the role of these CXC and CC chemokines and their receptors in patients with UC, CD, and normal controls (NC). Methods We studied constitutive and inflammation-induced expression and production of CXCR3 and CCR3 together with their ligands in the colon and CD3+ peripheral blood lymphocytes of patients with inflammatory bowel diseases (IBD) by flow cytometry, reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We further defined the regulated expression of these chemokines by RT-PCR and ELISA using cultured human epithelial cell lines. Thus, HT-29 and Caco-2 colonic epithelial cells were studied following in vitro stimulation with pro-inflammatory (Th1) and Th2-derived cytokines. Results CXCR3A mRNA (full size) expression was found in CD3+ PBL from normal controls and UC patients, but not from CD patients. In contrast, CD3+ PBL from CD patients showed a marked mRNA expression of the spliced variant CXCR3B. This finding could explain the high expression of CXCR3 on CD3+ PBL from CD patients in flow cytometry. Increased chemokines expression and production was found in colonic biopsies and serum from CD compared to UC patients and normal controls. Stimulation of epithelial cells with Th1 proinflammatory cytokines significantly induced chemokines production. The addition of Th2-derived cytokines had an inhibitory effect. Stimulation of Jurkat cells with cytokines and supernatant conditioned media from epithelial cells induced CXCR3A or CXCR3B expression depending on the stimuli. When CC chemokines were examined, a higher fraction of peripheral T lymphocytes were found to be positive for CCR3 in patients with ulcerative colitis (UC) compared to Crohn’s Disease (CD) whilst almost no CCR3+ T cells were found in normal controls (NC). Similarly, higher and more frequent expression of CCR3 was observed in colonic biopsies from patients with UC-regardless of the disease activity-when compared to CD or NCs. Serum CCL11/Eotaxin-1 was significantly increased in UC (306±87pg/ml) and less so in CD (257±43pg/ml) whereas CCL24/Eotaxin-2, and CCL26/Eotaxin-3 were increased only in UC. Colonic expression of the three chemokines was minimal in NCs but high in IBD (especially UC) and was independent of disease activity. Th2 and to a lesser extent Th1 cytokines were able to induce expression and production of all three eotaxins from colonic epithelial cells in culture. Conclusions These data demonstrate that PBL from CD patients express a spliced variant of the CXCR3 receptor and suggests that epithelium can play a role in modulating pathologic T cell–mediated mucosal inflammation. Furthermore CCR3 and ligands over-expression would appear to be a characteristic of UC. The production of CCR3 ligands by human colonic epithelial cells further supports the important role of epithelium – lymphocyte interaction in the pathogenesis of IBDΤα κολονικά επιθηλιακά κύτταρα του εντέρου εκφράζουν χημειοκίνες σχετιζόμενες με την Th1 ανοσολογική απόκριση. Ωστόσο λίγα είναι γνωστά για τον ρόλο των επιθηλιακών κυττάρων στην Th2 ανοσολογική αντίδραση. Επιπλέον η μετανάστευση των Τ λεμφοκυττάρων, τα οποία εκφράζουν στην επιφάνειά τους υποδοχείς χημειοκινών, προς το κολονικό επιθήλιο εμπλέκεται στην αιτιοπαθογένεια της Crohn και Ελκώδους Κολίτιδας. Μελετήσαμε την έκφραση των CXC χημειοκινών MIG, IP-10, και I-TAC οι οποίες προσδένονται στον CXCR3A υποδοχέα των Th1 κυκλοφορούντων λεμφοκυττάρων ή στο μεταγραφικό του αλλήλιο CXCR3B αλλά και των CC χημειοκινών, CCL11/Eotaxin-1, CCL24/Eotaxin-2, και CCL26/Eotaxin-3 οι οποίες προσδένονται στον CCR3 υποδοχέα των Τh2 κυκλοφορούντων λεμφοκυττάρων σε ασθενείς με Νόσο Crohn, Ελκώδη Κολίτιδα και σε υγιείς μάρτυρες. Αποτελέσματα Tα mRNA των τριών CXCR3 συνδεόμενων χημειοκινών (MIG, IP-10 και ITAC) ανευρίσκονται αυξημένα σε βιοψίες παχέος εντέρου ασθενών με Νόσο Crohn (CD). Παρομοίως ανευρίσκονται αυξημένα τα επίπεδα των MIG και ITAC χημειοκινών στον ορό των ασθενών με Νόσο Crohn και λιγότερο με Ελκώδη Κολίτιδα σε σχέση με τους υγιείς μάρτυρες. In vitro πειράματα σε κολονικά επιθηλιακά κύτταρα έδειξαν επαγωγή της έκφρασης mRNA και της παραγωγής των τριών χημειοκινών MIG, IP-10 και I-TAC και στις δύο κυτταρικές σειρές μετά από επίδραση Th1 κυτταροκινών. Επίδραση των Τh2 αντιφλεγμονωδών κυτταροκινών (IL-4, IL-10, IL-13) στην επαγόμενη από τις Th1 κυτταροκίνες (IL-1α, TNF-α και IFN-γ) έκφραση των τριών CXCR3 συνδεόμενων χημειοκινών είχε ως αποτέλεσμα την αναστολή της έκφρασης και παραγωγής των χημειοκινών αυτών και στις δύο επιθηλιακές κυτταρικές σειρές. Ο υποδοχέας των χημειοκινών αυτών, CXCR3 ανιχνεύτηκε σημαντικά αυξημένος με κυτταρομετρία ροής σε CD3+ ανοσομαγνητικά διαχωρισθέντα περιφερικά λεμφοκύτταρα ασθενών με Νόσο Crohn και λιγότερο με Ελκώδη Κολίτιδα σε σχέση με τους υγιείς μάρτυρες. Σε ανοσομαγνητικά διαχωρισθέντα CD3+ περιφερικά λεμφοκύτταρα από ασθενείς με Νόσο Crohn παρατηρήθηκε κυρίως έκφραση mRNA του μεταγραφικού αλληλίου CXCR3Β υποδοχέα, Αντίθετα υγιείς μάρτυρες εξέφραζαν κυρίως το mRNA του CXCR3Α ενώ στην Ελκώδη Κολίτιδα παρατηρήθηκε παρόμοια έκφραση CXCR3Α και CXCR3Β. In vitro επιδράσεις στη λευχαιμική κυτταρική σειρά Jurkat έδειξαν επαγωγή των CXCR3Α και CXCR3Β mRNAs μετά από επίδραση με IFN-γ, ενώ η IL-1α προκαλούσε επαγωγή μόνο του CXCR3Β mRNA. Επίδραση TNF-α είχε ως αποτέλεσμα επαγωγή του CXCR3Α. Όσον αφορά τις CC χημειοκίνες, σε βιοψίες παχέoς εντέρου παρατηρήθηκε σημαντική αύξηση του mRNA και των τριών CCR3 συνδεόμενων χημειοκινών – CCL11 (eotaxin), CCL24 (eotaxin 2) και CCL26 (eotaxin 3) - σε ιστούς ασθενών με Ελκώδη Κολίτιδα σε σχέση με φυσιολογικούς μάρτυρες και ασθενείς με Νόσο Crohn. Συνολικά και οι τρεις χημειοκίνες που συνδέονται στον CCR3 υποδοχέα βρέθηκαν αυξημένες στον ορό ασθενών με Ελκώδη Κολίτιδα. Κατόπιν μελετήσαμε in vitro στις HT-29 και Caco-2 κυτταρικές σειρές την έκφραση mRNA και την παραγωγή των χημειοκινών αυτών μετά από επίδραση κυτταροκινών. Επίδραση του συνδυασμού των Th1 κυτταροκινών είχε ως αποτέλεσμα αύξηση του mRNA της CCL26/Eotaxin-3 και στις δύο κυτταρικές σειρές καθώς και των χημειοκινών CCL11/Eotaxin-1 και CCL24/Eotaxin-2 σε μικρότερο βαθμό. Επίδραση με το συνδυασμό των προφλεγμωνωδών κυτταροκινών Th2 προκάλεσε σημαντική επαγωγή mRNA και των τριών χημειοκινών, CCL11/Eotaxin-1 και στις δύο κυτταρικές σειρές. Αλλά και σε επίπεδο πρωτεΐνης, οι Th2 προφλεγμονώδεις κυτταροκίνες σε συνδυασμό επάγουν την παραγωγή των CCR3 συνδεόμενων χημειοκινών και στις δύο κολονικές επιθηλιακές κυτταροσειρές. Όσον αφορά τον υποδοχέα των χημειοκινών αυτών CCR3, η έκφραση του mRNA ήταν μέγιστη σε βιοψίες κολονικού βλεννογόνου ασθενών με Ελκώδη Κολίτιδα (95%), σε σχέση με φυσιολογικούς μάρτυρες (20%). Έκφραση παρατηρήθηκε και στο 65% των ασθενών με Νόσο Crohn. Η έκφραση αυτή παρουσιάζονταν ανεξάρτητα από την ενεργότητα της νόσου και το βαθμό φλεγμονής του κολονικού βλεννογόνου. Η κυτταρομετρία ροής σε ανοσομαγνητικά διαχωρισθέντα CD3+ κύτταρα ανέδειξε έκφραση του υποδοχέα CCR3 κυρίως σε ασθενείς με Ελκώδη Κολίτιδα, λιγότερο σε Νόσο Crohn και σχεδόν καθόλου σε υγιείς μάρτυρες. Συμπεράσματα Στη μελέτη μας παρατηρήθηκε αυξημένη έκφραση του CXCR3 υποδοχέα σε ανοσομαγνητικά διαχωρισθέντα CD3+ λεμφοκύτταρα περιφερικού αίματος από ασθενείς με Νόσο Crohn και Ελκώδη Κολίτιδα σε σύγκριση με φυσιολογικούς μάρτυρες. Αυτή η έκφραση ήταν υψηλότερη στους ασθενείς με Νόσο Crohn οι οποίοι εξέφραζαν το mRNA του μεταγραφικού αλληλίου CXCR3B. Επιπρόσθετα, η έκφραση των CCR3 συνδεόμενω

Automated Detection of Liver Histopathological Findings Based on Biopsy Image Processing

Hepatic steatosis is the accumulation of fat in the hepatic cells and the liver. Triglycerides and other kinds of molecules are included in the lipids. When there is some defect in the process, hepatic steatosis arise, during which the free fatty acids are taken by the liver and exuded as lipoproteins. Alcohol is the main cause of steatosis when excessive amounts are consumed for a long period of time. In many cases, steatosis can lead to inflammation that is mentioned as steatohepatitis or non-alcoholic steatohepatitis (NASH), which can later lead to fibrosis and finally cirrhosis. For automated detection and quantification of hepatic steatosis, a novel two-stage methodology is developed in this study. Initially, the image is processed in order to become more suitable for the detection of fat regions and steatosis quantification. In the second stage, initial candidate image regions are detected, and then they are either validated or discarded based on a series of criteria. The methodology is based on liver biopsy image analysis, and has been tested using 40 liver biopsy images obtained from patients who suffer from hepatitis C. The obtained results indicate that the proposed methodology can accurately assess liver steatosis