Introduction

Recurrent non-stenotic cholangitis (NSC) is a challenging and poorly understood complication of a surgical hepaticojejunostomy (HJ).¹ Optimal treatment remains unclear as etiology of NSC is unknown and large series are lacking.^2,3,4

Aims & Methods

This study aims to analyze a tertiary single center's experience in managing patients diagnosed with recurrent NSC in preparation for a future multicenter prospective study. A retrospective single center series including patients with recurrent NSC after surgery with HJ (2015-2022) was conducted. Patients with HJ stenosis were excluded. Primary outcome was resolution of NSC (i.e. free of NSC during six months). Secondary outcomes included reduction of NSC monthly episode frequency and secondary sclerosing cholangitis.

Results

Overall, 50 of 1179 (4.2%) patients with HJ developed NSC. Index surgery was mostly pancreatoduodenectomy (n=35, 70%). Treatment included a ‘step-up approach’ with short-course antibiotics (n=50, 100%), prolonged antibiotics (n=26, 52%), and revisional surgery (n=7, 14%). During a median follow-up of 42.5 months (IQR 23.5-60), patients experienced a median of 7 (IQR 4-9.2) recurrent NSC episodes, requiring hospitalization in 29 patients (58%). Resolution of NSC was achieved in 15 patients (30%) and reduction of NSC frequency in an additional 21 patients (42%). Concomitant ursodeoxycholic acid use and discontinuation of proton pump inhibitors was the only predictor for resolution (OR 4.229, p=0.035). Secondary sclerosing cholangitis occurred in 12 patients (24%) and was associated with the number of NSC episodes (OR 1.2, p=0.050).

Conclusion

A ‘step-up approach’ to recurrent NSC after HJ resulted in 30% resolution and further 42% reduced frequency of NSC although still a quarter of patients developed secondary sclerosing cholangitis. Future prospective studies should assess whether a protocolized approach could improve outcomes.

References

1. Birgin E, Téoule P, Galata C, Rahbari NN, Reissfelder C. Cholangitis following biliary-enteric anastomosis: A systematic review and meta-analysis. Pancreatology. 2020 Jun;20(4):736-745. doi: 10.1016/j.pan.2020.04.017. Epub 2020 Apr 30. PMID: 32386969.
2. Overdevest AG, Fritzsche JA, Smit MAD, Besselink MG, Bonomi AM, Busch OR, Daams F, van Delden OM, Kazemier G, Langver J, Ponsioen CY, Swijnenburg RJ, van Wanrooij RLJ, Wielenga MCB, Zonderhuis BM, Zijlstra IAJ, Erdmann JI, Voermans RP. Recurrent cholangitis in patients with a non-stenotic hepaticojejunostomy: incidence and risk factors. HPB (Oxford). 2024 Jan 7:S1365-182X(24)00003-0. doi: 10.1016/j.hpb.2024.01.003. PMID: 38245491.
3. van den Hazel SJ, Speelman P, Tytgat GN, van Leeuwen DJ. Successful treatment of recurrent cholangitis with antibiotic maintenance therapy. Eur J Clin Microbiol Infect Dis. 1994 Aug;13(8):662-5. doi: 10.1007/BF01973995. PMID: 7813499.
4. Matthews JB, Baer HU, Schweizer WP, Gertsch P, Carrel T, Blumgart LH. Recurrent cholangitis with and without anastomotic stricture after biliary-enteric bypass. Arch Surg. 1993 Mar;128(3):269-72. doi: 10.1001/archsurg.1993.01420150023004. PMID: 8442681.

Disclosure

Alessandro M. Bonomi, Anouk G. Overdevest, Jeska A. Fritzsche, Olivier R. Busch, Rutger-Jan Swijnenburg, Babs M. Zonderhuis, Ulrich Beuers and Joris I. Erdmann have no conflicts of interest or financial ties to disclose.
Freek Daams reports speaker fees, consultancy fees and research support from Medtronic, research support from Hak foundation outside of the current project.
Marc G. Besselink has received research support from Intuitive Surgery, Medtronic, Ethicon and acted as proctor for Intuitive Surgical.
Geert Kazemier reports research support and travel fees from SAS Analytics and research grants from KWF, ZonMw, Cancer Center Amsterdam Foundation, and Bennink Foundation outside the submitted research.
Roy L.J. van Wanrooij performed as a consultant for Boston Scientific.
Rogier P. Voermans reports research grants from Boston Scientific and Prion Medical, performed as a consultant for Boston Scientific and Cook Medical, and received speaker’s fee from Mylan and Zambon.
All outside the submitted work.

Introduction

Currently, there is no approved medication for the treatment of Metabolic Associated Fatty Liver Disease (MASLD). However, numerous clinical trials have examined the effect of antihyperglycemic agents on MASLD in type 2 diabetic (T2D) patients, given the close association between T2D and this hepatopathy, both of which are closely linked to insulin resistance. Our aim is to evaluate and compare the therapeutic effects of different hypoglycemic agents in patients with MASLD and T2D.

Aims & Methods

This is a prospective cross-sectional study involving 200 T2D patients over a 6-month period. The presence of hepatic steatosis was confirmed by abdominal ultrasound and/or a Fatty Liver Index (FLI) score greater than 60 in 122 patients. Hepatic fibrosis was assessed using FibroScan in all patients with MASLD. Two comparative studies were conducted to identify the therapeutic effects of hypoglycemic medications on hepatic steatosis and significant fibrosis, defined by a LSM value ≥ 8 kPa.

Results

Patients were predominantly female (73.2%) with a median age of 59.76 ± 10 years. The duration of T2D, although longer in cases of steatosis, was not statistically significant. Glycemic control, assessed by fasting blood glucose and HbA1c levels, was less optimal in patients with MASLD, with an average HbA1c level of 8.98%, compared to patients without hepatic steatosis, who had an average HbA1c level of 8.74% (p=0.002). A similar trend was observed with fasting blood glucose levels (81.96% vs 73.07%), but it did not reach statistical significance.

Degenerative complications, regardless of their type, were comparable between the two groups.

The prescription of biguanides was associated with a reduced risk of hepatic steatosis (p=0.05), while insulin use was frequently observed in patients with steatosis, with a statistically significant correlation for long-acting human insulin and rapid-acting analogs (33.61% vs 19.23% in the absence of steatosis, p=0.02) and (4.92% vs 0% in the absence of steatosis, p=0.05) respectively. No other therapeutic modality, including different classes of oral antidiabetic agents, was correlated with the risk of steatosis.

The prescription of sulfonylureas and rapid-acting insulin analogs was associated with a higher risk of significant hepatic fibrosis, with p-values of 0.05 and 0.008 respectively. In contrast, the use of long-acting human insulin was less frequent in patients with significant fibrosis, with a statistical correlation of 0.03. No other treatment modality, including various types of oral antidiabetic agents, was associated with the risk of fibrosis.

Conclusion

The use of biguanides appears to reduce the risk of hepatic steatosis, while insulin therapy, particularly rapid-acting analogs, is associated with an increased risk of hepatic steatosis and fibrosis. These observations emphasize the importance of an individualized therapeutic approach to optimize the management of MASLD in type 2 diabetic patients. Further studies are needed to validate these associations

References

Tang W, Xu Q, Hong T, Tong G, Feng W, Shen S, et al. Comparative efficacy of anti‐diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta‐analysis of randomized and non‐randomized studies. Diabetes Metabolism Res. févr 2016;32(2):200‑16.

Yan J, Yao B, Kuang H, Yang X, Huang Q, Hong T, et al. Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Hepatology. juin 2019;69(6):2414‑26.

Introduction

Acute cellular rejection (ACR) remains a common complication causing significant morbidity after liver transplantation.^1,2 Recent studies suggest that the proportion of non-HLA mismatched SNPs, referring to all SNPs outside the HLA region, also known as major histocompatibility complex (MHC), was associated with increased rejection risk after kidney transplantation.^3-6 This is currently unexplored in liver transplantation.

Aims & Methods

We aimed to investigate whether donor-recipient non-HLA genetic mismatch is associated with increased incidence of biopsy-proven grade 2/3 ACR, hereafter referred to solely as ACR, within 1-year after liver transplantation. We conducted an international multicenter case-control genome-wide association study of donor and liver transplant recipient pairs in three independent cohorts, totaling 1846 pairs. To assess the burden of donor-recipient genetic incompatibility, we calculated sum scores for single nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs. Additionally, we performed an analysis specifically including only SNPs coding for transmembrane or secreted proteins, which are more likely to affect the immune system. We analyzed the association between the log-normalized non-HLA mismatch scores and ACR in a multivariable cox regression model per cohort, followed by a weighted meta-analysis.

Results

During the first-year post-transplantation, 90 of 689 (13%), 161 of 720 (22%) and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. After correcting for potential confounders using multivariable cox regression analysis, our weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with increased incidence of 1-year ACR (HR 5.31; 95%CI 1.39-20.08; P=0.015). Moreover, we also confirmed the effect of mismatch in the subset of SNPs coding only for transmembrane or secreted proteins on 1-year ACR (HR 6.69; 95%CI 1.82-24.78; P=0.004).

Conclusion

In this multi-center genome-wide meta-analysis we show that genetic non-HLA incompatibility between donors and recipients is an important independent predictor of ACR after liver transplantation. Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs coding for transmembrane or secreted proteins correlated with ACR developed within the first year after liver transplantation. Identifying high-risk immunological burden between donor-recipient pairs may potentially prevent early graft rejection and help future efforts to personalize immuno-suppressive medication. This is important as immune suppressive medication causes significant morbidity and mortality.

References

1. Burra P. The adolescent and liver transplantation. J Hepatol. 2012; doi:10.1016/j.jhep.2011.07.032
2. Choudhary NS, Saigal S, Bansal RK, et al. Acute and Chronic Rejection After Liver Transplantation: What A Clinician Needs to Know. J Clin Exp Hepatol. 2017; doi:10.1016/j.jceh.2017.10.003
3. Reindl-Schwaighofer R, Heinzel A, Kainz A, et al. Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort. Lancet. 2019; doi:10.1016/S0140-6736(18)32473-5
4. Pineda S, Sigdel TK, Chen J, et al. Novel non-histocompatibility antigen mismatched variants improve the ability to predict antibody-mediated rejection risk in kidney transplant. Front Immunol. 2017; doi:10.3389/fimmu.2017.01687
5. Steers NJ, Li Y, Drace Z, et al. Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection. N Engl J Med. 2019; 380(20):1918-1928. doi: 10.1056/NEJMoa1803731. PMID: 31091373; PMCID: PMC6589355.
6. Markkinen S, Helanterä I, Lauronen J, et al. Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation. Kidney Int Rep. 2022; 7(11):2484-2494. doi: 10.1016/j.ekir.2022.08.032. PMID: 36531875; PMCID:

Introduction

Since 2010 (1), little data has been available in France on the management of severe acute alcoholic hepatitis (SAH). In order to obtain a current "mapping" of the management of severe HAS in France, a practice survey was conducted from 04/2022 to 07/2023.

Aims & Methods

A Google questionnaire pre-established by a working group was sent to all the hepatogastroenterology departments of general hospitals (nUH), the hepatology departments of university hospitals (UH). The results are expressed as means ± SD. Data analysed: demographics, type of practice (university hospital, general hospital), predominant speciality, experience, number of AA treated per centre with corticosteroids (C) or N-acetylcysteine corticosteroids (NAC). Existence of an AA treatment protocol. Systematic use of transjugular liver biopsy (LB), on-site LB, time taken to obtain results. Treatment: use of C alone or C-NAC. Screening for bacterial infections, use of antibiotic therapy (ATB) in the event of infection, time taken to start treatment for AA. Whether or not to use C in antigen-positive HBs patients (with or without pre-emptive treatment). Interruption of C in the event of an intermediate Lille score at D7. Indication for transfer to a liver transplant centre.

Results

465 respondents (R): 40 years (12.5); 50% M, 50% F, UH 53.3%, nUH 46.7%, hepatologists 57%, gastroenterologists 39%, juniors 21%. Number of AA treated with CS or CS NAC 25 (0 to 300); the number of AA treated in UH was higher than in non UH: 34 (29), nUH 15.4 (13.4), p < 0.001. Treatment protocol for AA, 62% (University Hospital) vs 42% (Hospital), p < 0.001. LB systematically performed: 98% AA vs 50% other, p < 0.001. Time taken to obtain LB (days): 3.4 (UH) vs 4.9 (nUH), p < 0.001. Nutritional status was assessed by 98% of patients. A systematic chest CT scan was routinely requested by 34% of patients in the event of suspected pulmonary infection (UH versus nUH ns); 83% of patients waited 4 days (2-6) before starting treatment in the event of documented infection. Treatment: C alone 70% of patients (UH vs nUH ns), NAC use: UH 40% vs nUH 47.3% (ns). Treatment protocol for alcohol withdrawal syndrome: 86.3% nUH vs 76.3% UH (p < 0.01). CS stopped in the event of an intermediate Lille score at D7: 80% nUH vs 77% UH; ns. 69% of R's were responsible for initiating treatment. 68.2% of R were responsible for initiating treatment; 64.7% in UH vs 72.3% (NS); 80.6% senior doctors vs 20.4% junior doctors (p<0.001). 62% of R used pre-emptive treatment before CS in the case of a positive HBs antigen; 59.4% in UH vs 65% in nUH (p=0.004) and 76% used upper gastrointestinal endoscopy if there had been none previously, 77% in UH vs 75% nUH (p=0.782).

Conclusion

The results of this study of national practice carried out in a large sample of doctors practising in or outside university hospitals show a disparity in the use of LB in cases of suspected severe AA, since 50% of R outside university hospitals do not use LB, mainly because of the absence of local possibilities. Dual C-NAC therapy is used fairly frequently. There is a disparity between university hospitals and general hospitals in the management of alcohol withdrawal syndrome and pre-emptive treatment in cases of positive HBs antigen. This study provides an update on the management of severe AA in France.

References

E.Nguyen-Khac et al J Hepatol 2010 (abstract)

Introduction

The treatments for liver fibrosis are still in need so far. As the crucial initiators, activated hepatic stellate cells (aHSCs) undergo a series of epigenetic changes. The study intends to explore transcription factors (TFs) that facilitate HSCs activation and provide novel therapeutic targets for liver fibrosis.

Aims & Methods

Three distinct HSCs activation models were established in present study. Firstly, in vitro activation involved isolating primary HSCs from normal Sprague-Dawley rats and culturing them for two days (n=5) and seven days (n=5), namely natural activation model. Secondly, in vivo activation entailed isolating primary HSCs from bile duct ligated rats (n=4) and normal controls (n=4), followed by culturing until the next day. Lastly, transforming growth factor-β (TGF-β, 2.5ng/ml) (n=10) or control buffer (n=10) were added to the human HSCs cell line LX2 and cultured for 24 hours. Subsequently, assay for transposase-accessible chromatin using sequencing (ATAC-seq) was conducted on the abovementioned cells, along with motif enrichment and footprint analysis. Pathway enrichment analysis was performed on differentially accessible genes (DAGs). RNA sequencing (RNA-seq) was employed to analyze gene expression profiles of primary HSCs in the natural activation model (n=4). The integration of ATAC-seq and RNA-seq further identified potential key TFs. RT-qPCR and differential expression analysis of public datasets was utilized to confirm the dysregulation of TFs in primary HSCs, fibrotic liver and fibrotic model of induced pluripotent stem cells. Finally, enrichment at enhancers and promoters of these genes was validated by H3K27Ac and H3K4me3 chromatin immunoprecipitation followed by sequencing (ChIP-seq) of human HSCs.

Results

For ATAC-seq, primary HSCs exhibited higher chromatin accessibility after activation compared with the controls. After peak annotation, the up-regulated peaks were mainly located in the promoter region in all comparison groups, uncovering the dynamic transcriptional regulation during HSC activation. In the motif enrichment analysis, 150 aHSCs related TFs and 54 quiescent HSCs (qHSCs) related TFs were identified in the in vitro activation model. The three models shared 12 aHSCs related TFs, namely Runx-aml, Runx1, Runx2, Runx, Ets:Runx, Atf2, Atf4, Atf7, c-Jun-Cre, Creb5, Smad3 and CArG; and 19 qHSCs related TFs, including Foxf1, Foxo3, Foxk1, Foxp1, Hoxa1, Hoxa2, Stat3, Hnf4a, Hnf6, Elk1, Elk4, Cux1, Crx, Duxbl, Vdr, Tr4, Ebf2, Gata2, Gata6. Footprint analysis validated the alteration of accessibility in Atf2, Atf4, Atf7, Creb5, Hnf6 and Gata2. Actin filament organization, Ras protein signal transduction and intrinsic apoptotic signal pathways were enriched in DAGs. Integration of ATAC-seq and RNA-seq showed that gene expression was significantly correlated with chromatin accessibility, among which Runx2, Creb5, and Smad3 were significantly upregulated in aHSCs at transcription level. The dysregulation of these three genes was verified in primary HSCs, fibrotic liver and fibrotic model of human induced pluripotent stem cells. Finally, enrichment at active enhancers and promoters of these TFs was validated by H3K27Ac and H3K4me3 ChIP-seq of human HSCs, revealing the crucial role of genes in the transcription.

Conclusion

We generated chromatin accessibility profiles of different HSCs activation models, highlighting the significance of Runx2, Creb5, and Smad3 as key TFs mediating HSCs activation. These findings proposed these TFs as promising targets for future liver fibrosis treatment.

Disclosure

The author declare no competing interests and financial relationships with commercial interests.

Introduction

Periampullary diverticulum (PAD) is associated with a higher incidence of biliary stone formation and common bile duct (CBD) obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) is an effective therapeutic procedure in case of biliary obstruction, however; the presence of PAD and its different types could affect ERCP outcome [1-3].

Aims & Methods

Aim: To study the impact of periampullary diverticulum on the outcome of ERCP regarding the cannulation technique, the procedure time, the success rate and the complications.
Method: A Retrospective study included all patients subjected to ERCP procedures at Qena university hospitals, South Valley University, Qena, Egypt from February 2019 to August 2023. ERCP Will be performed under general anaesthesia with endotracheal intubation according to our centre policy by an expert ERCP endoscopist using Pentax duodenoscopy (ED-3490TK, Pentax Incorporation, Tokyo, Japan). Papilla of vater will be examined endoscopically before starting cannulation trials to evaluate presence of diverticulum, type, size and its relation to the papilla. Data were analyzed using Statistics Package for Social Sciences (SPSS) version 26, p-value < 0.05 was considered significant.

Results

A Total of 686 patients subjected to ERCP procedure for different indications were included in this study, males were 273 patients (39.8%), the mean age was 53.7±17 years, the overall procedure success rate was 91% and the overall complications rate was 6%. Almost all cannulation techniques were used in our cases including wire-guided cannulation (WGC), transpapillary fistulotomy (TPF), double-guidewire technique (DGT), transpapillary papillotomy (TPP), and transpancreatic septotomy with pancreatic stent insertion (TPS). PAD was detected during ERCP procedure in 61 patients (9%). There was statistically significant higher age (65.3 vs 52.6, p< 0.001) and statistically insignificant higher frequency of males (41% versus 39.7%, p₌ 0.8) in patients with PAD compared to patients without PAD. During ERCP procedures, presence of PAD was associated with higher number of cannulation attempts (3.5 versus 2.5, p< 0.005), longer time required for cannulation (8 vs 5.1 minutes, p< 0.01), and amazingly; higher rate of cannulation success (100% vs 98%, p₌ 0.2), and longer total procedure time (50.4 ± 21.9 minutes vs 47.01 ± 24.04, p₌ 0.2). There was no significant predilection of certain cannulation technique in PAD patients; higher WGC: 68% vs 67%, higher TPS (1.8% vs 0.5%), equal chance for WGC: 24.6% vs 24.6% and less chance for TPP: 0.7 vs 0%. The overall procedure success rate was lower in PAD patients (85.2% vs 91.2%, p₌ 0.1). Post-ERCP pain was noticed more frequently in PAD patients (4.9% vs 3.4%, p₌ 0.5) while the overall complication rate with lower (1.6% vs 6.4%, p₌ 0.1).

Conclusion

We concluded that PAD is increasingly detected during ERCP procedure in elderly patients, and despite it requires higher number of cannulation attempts and longer time for cannulation, it has no negative impact on the overall success rate or complication rate of ERCP.

References

1. Chen L, Xia L, Lu Y, Bie L, Gong B. Influence of periampullary diverticulum on the occurrence of pancreaticobiliary diseases and outcomes of endoscopic retrograde cholangiopancreatography. Eur J Gastroenterol Hepatol. 2017;29:105–11.
2. Banerjee AK, Celentano V, Khan J, Longcroft-Wheaton G, Quine A, Bhandari P. Practical gastrointestinal investigation of iron deficiency anaemia:i] Expert Rev Gastroenterol Hepatol. 2018;12(3):249-256.
3. Omar MA. Effect of periampullary diverticulum on technical success and complications of endoscopic retrograde cholangiopancreatography: Single center experience. J Dig Endosc. 2015;6:149–57