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IMPACT OF HEPATIC AND SYSTEMIC INFLAMMATION ON THE DYNAMIC COMPONENT OF PORTAL HYPERTENSION DURING DISEASE REGRESSION IN ALCOHOL-RELATED CIRRHOSIS

Benedikt Hofer 1,2,3, Benedikt Simbrunner 1,2,3, Kerstin Zinober 1,2, Georg Semmler 1,2, Philipp Königshofer 1,2,3, Oleksandr Petrenko 1,2,3, Thomas Sorz 1,2,3, Vlad Taru 1,2, Michael Trauner 1, Mattias Mandorfer 1,2, Philipp Schwabl 1,2,3, Thomas Reiberger 1,2,3

Affiliations

1 Medical University Of Vienna, Vienna, Austria

2 Medical University of Vienna, Vienna, Austria

3 Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria

Summary

AI Generated

Inflammation remains a critical determinant of the dynamic component of portal hypertension in both mouse models and abstinent patients with alcohol-related liver cirrhosis despite significant improvements during disease regression.

In mouse models of cirrhosis regression, increased intrahepatic expression of inflammatory genes (Tnfα, Il6, Il1β, Cxcl1, Mcp1) was significantly associated with higher-than-expected portal pressure levels beyond what would be predicted by the degree of fibrosis alone.
In 128 abstinent alcohol-related liver cirrhosis patients, longer abstinence duration correlated with lower HVPG, liver stiffness, IL-6, and CRP, yet patients with higher systemic inflammation (IL-6, CRP) demonstrated higher HVPG than predicted by liver stiffness measurement.
Decreased complement factors C3c and C4 were associated with higher-than-expected HVPG in patients, with the negative C3c correlation present only in short-term abstinence (≤6 months) while systemic inflammation effects were primarily seen in long-term abstinence (>6 months).
The study used linear modeling to separate static (fibrosis-related) from dynamic (inflammation-related) components of portal hypertension by comparing predicted versus measured portal pressure in both experimental systems.
This work is relevant to researchers investigating portal hypertension mechanisms and clinicians managing patients with regressing liver disease who wish to understand factors beyond fibrosis that influence portal pressure.

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Portal hypertension (PH), a key driver of liver-related morbidity, arises as a consequence of static and dynamic changes in the liver parenchyma. While the static PH component is determined by the degree of fibrosis, the analysis of dynamic PH components remains challenging.

Aims & Methods

We aimed to investigate the influence of inflammation on the dynamic component of PH in the setting of liver disease regression in (i) well-standardised mouse models and (ii) abstinent patients with alcohol-related liver cirrhosis (ALD). In male C57BL/6JRj mice, disease regression was modelled by administering carbon tetrachloride or thioacetamide for 12 weeks to induce cirrhosis before discontinuing the toxic stimulus and thus enabling regression for either one (R1; n=15) or two (R2; n=15) weeks. In our patient cohort, we included 128 ALD patients with prolonged abstinence (>1 month) undergoing same-day hepatic venous pressure gradient (HVPG) and liver stiffness measurement (LSM). The static component of PH during regression (histological collagen proportionate area [CPA; %] in mice; LSM in patients) was used to predict portal pressure (PP) based on a linear model. Subsequently, we explored parameters affecting the dynamic PH component (i.e., difference between the predicted PP based on LSM/CPA and the true/measured PP) by analysing the linear model’s residuals.

Results

When compared to mice at peak disease severity, withdrawing the toxic stimulus led to a significant decrease in PP, CPA and intrahepatic expression of inflammatory genes (see Table). Despite improvements in hepatic inflammation during regression, the linear model demonstrated a significant association between an increased expression of inflammatory genes and higher-than-expected PP levels in R1 and R2 mice, as shown by the positive correlation between Tnfα (Spearman’s r:0.46; p=0.012), Il6 (r:0.48; p=0.008), Il1β (r:0.39; p=0.036), Cxcl1 (r:0.33; p=0.075) and Mcp1 (r:0.26; p=0.159) with the model’s residuals. Similarly, a longer duration of abstinence in ALD patients was associated with a significantly lower HVPG (r:-0.21; p=0.017), LSM (r:-0.37; p<0.001), IL-6 (r:-0.24; p=0.006) and CRP (r:-0.28; p=0.001). Nevertheless, patients with higher levels of systemic inflammation also demonstrated a higher HVPG than predicted by LSM in the linear model. Specifically, IL-6 (r:0.18; p=0.043) and CRP (r:0.21; p=0.016) were positively correlated with the model’s residuals. Furthermore, levels of complement factor C3c (r:-0.22, p=0.049) and C4 (r:-0.15, p=0.203) were markedly decreased in patients with higher-than-expected HVPG. Interestingly, while the impact of systemic inflammation was primarily found in long-term abstinence (>6 months), the negative correlation with C3c was only present in short-term abstinence (≤6 months).

	Healthy animals n=13	Diseased animals n=14	R1 n=15	R2 n=15	p-value
PP (mmHg)	5.4 (5.2-5.7)	8.3 (7.7-9.9)	7.7 (7.2-8.2)	6.4 (6.0-8.1)	<0.001
CPA (%)	0.77 (0.73-0.97)	4.35 (3.79-16.20)	4.33 (3.58-9.74)	3.29 (2.94-5.09)	<0.001
Tnfa (log₂ fold change)	0.00±0.50	2.96±0.71	1.92±0.57	1.98±0.92	<0.001
Il6 (log₂ fold change)	0.00±0.91	1.39±1.34	-0.69±1.27	0.04±1.26	<0.001
Cxcl1 (log₂ fold change)	0.00±0.72	1.52±0.74	-0.16±0.71	-0.16±0.78	<0.001
Il1b (log₂ fold change)	0.00±0.44	0.33±0.43	0.10±0.55	0.77±1.09	0.021
Mcp1 (log₂ fold change)	0.00±0.57	3.77±1.23	1.50±0.63	0.87±1.02	<0.001

Conclusion

Despite significant improvements during disease regression, intrahepatic inflammation in mice and systemic inflammation in ALD patients remain critical determinants of the dynamic component of PH.

Disclosure

Benedikt Simbrunner: Travel support from AbbVie and Gilead. Georg Semmler: Travel Support from Gilead. Michael Trauner: Grant support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and UltraGenyx; Honoraria for consulting from Albireo, Boehringer Ingelheim, BiomX, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, Pliant, Regulus and Shire; Speaker fees from Bristol-Myers Squibb, Falk, Gilead, Intercept and MSD; Travel support from AbbVie, Falk, Gilead and Intercept. Mattias Mandorfer: Speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Gilead, and W. L. Gore & Associates; Travel support from AbbVie and Gilead. Philipp Schwabl: Consulting fees from PharmaIN; Travel support from Falk and Phenex Pharmaceuticals. Thomas Reiberger: Grant support from Abbvie, Boehringer-Ingelheim, Gilead, Gore, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, and Siemens; Speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; Consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; Travel support from Abbvie, Boehringer-Ingelheim, Gilead and Roche.

Conference

UEG Week Copenhagen 2023

Topics

Hepatobiliary

Submission format

Abstract

Session

PP 07 Liver & biliary (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Patient with an early rectal cancer detected by FIT-screening

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Patient with an early rectal cancer detected by FIT-screening

Leon M.G. Moons 1

Affiliations

1 University Medical Center Utrecht, Utrecht, Netherlands

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Abstract

Event

UEG Postgraduate Teaching Programme Vienna 2024

Topics

Colorectal Digestive Oncology Education & Training Endoscopy

Session

CRC: It's all about screening

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Summary: Cancer and IBD - Mitigating risk among uncertainty

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Summary: Cancer and IBD - Mitigating risk among uncertainty

Michael Schumann 1

Affiliations

1 Charité Berlin, Berlin, Germany

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Digestive Oncology IBD

Session

Cancer and IBD: Mitigating risk among uncertainty

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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The bum: Haemorrhoids, fissure disease, urgency and incontinence

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The bum: Haemorrhoids, fissure disease, urgency and incontinence

Dieter Hahnloser 1, Tatenda Marunda 2

Affiliations

1 CHUV, Lausanne, Switzerland

2 None, None, United Kingdom

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Abstract

Event

UEG Week Vienna 2024

Topics

Colorectal Primary Care

Session

My bum hurts: Painful proctology

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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How to handle high risk conditions for gastric cancer

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How to handle high risk conditions for gastric cancer

Judith Honing 1

Affiliations

1 Erasmus Mc, Rotterdam, Netherlands

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Colorectal Digestive Oncology Pancreas Stomach & H. Pylori

Session

Hereditary GI cancer syndromes: Surveillance strategies

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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REMIMAZOLAM IN ENDOSCOPY: A GAME-CHANGER FOR SAFE AND EFFECTIVE SEDATION IN REAL-WORLD PRACTICE

Alba Sparacino 1, Pietro Graceffa 1, Ivan Alberto Salerno 1, Fabio Cartabellotta 1, Fabio Cipolletta 2, Luigi Pasquale 2, Rosa Gallo 1, Luciano Calderone 1, Antonino Granata 1

Affiliations

1 Buccheri La Ferla Hospital, Palermo, Italy

2 Monaldi Hospital, Napoli, Italy

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Abstract

Introduction

Sedation is integral to gastrointestinal (GI) endoscopy to enhance procedural tolerance and efficiency [1]. Traditional agents like midazolam and propofol, while effective, present limitations related to recovery time, safety, and need for anesthesiologist supervision. Remimazolam, a novel benzodiazepine with rapid onset and offset, may enable effective non-anesthesiologist-administered sedation (NAAS) in routine endoscopy [2].

Aims & Methods

A prospective, multicenter, real-world study was conducted between November 2024 and March 2025. Adult patients undergoing elective upper or lower gastrointestinal (GI) endoscopy under procedural sedation-analgesia (PSA) without the presence of an anesthesiologist were enrolled. Inclusion criteria were: age ≥18 years, American Society of Anesthesiologists (ASA) physical status I–III, and a body mass index (BMI) between 18 and 51 kg/m². Exclusion criteria included: known allergy to anesthetic drugs or a history of anesthesia-related adverse reactions; glucose-6-phosphate dehydrogenase deficiency; severe respiratory disease; and pregnancy. All patients undergoing emergency or urgent GI endoscopy were excluded.The primary outcomes were the sedative efficacy and safety of remimazolam during endoscopy. Efficacy was defined as successful completion of the procedure without interruption due to inadequate sedation. Adverse events (AEs) were recorded and classified by severity (major or minor) and type (e.g., hypotension, hypoxia, bradycardia, nausea, vomiting, and injection site pain). Remimazolam was administered by trained endoscopists: induction was achieved with 5–7 mg intravenously, titrated based on individual risk factors, with 2.5 mg supplemental doses as needed (maximum cumulative dose: 33 mg).

Results

A total of 182 patients (EGD n=75; colonoscopy n=112) were included. Procedure completion was achieved in 175 cases (96.3%), with success rates of 97.3% for EGD and 95.5% for colonoscopy. All sedation failures (n=7) were attributed to inadequate sedation and not to ASA class. No serious AEs were reported. Minor AEs included hypotension (n=4), bradycardia (n=1), nausea (n=1), vomiting (n=4), and hiccups (n=1), all managed conservatively. Median cumulative remimazolam doses were 10.9 mg (colonoscopy) and 10.0 mg (EGD), with median recovery times of 6.25 and 5.9 minutes, respectively. No patients required flumazenil or rescue sedation. Among obese patients (BMI >40), remimazolam was both effective and safe.

Conclusion

Remimazolam provides a highly effective and safe sedation alternative for GI endoscopy in real-world NAAS settings, ensuring rapid recovery and minimal AEs, even in patients with elevated ASA status or obesity. This study was prospective real-world and had several limitations. First the number of patients was too small to accurately assess rare adverse events. Further randomized controlled trials with larger populations are recommended to confirm these results.

References

Lin OS. Sedation for routine gastrointestinal endoscopic procedures: a review on efficacy, safety, efficiency, cost and satisfaction. Intest Res 2017;15:456-66. doi: 10.5217/ir.2017.15.4.456.
Hu Q, Liu X, Wen C, et al. Remimazolam: an updated review of a new sedative and anaesthetic. Drug Des Devel Ther 2022;16:3957-74. doi: 10.2147/DDDT.S384155.

Conference

UEG Week Berlin 2025

Topics

Colorectal

Submission format

Abstract

Session

LOWER GI (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Leon M.G. Moons

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Judith Honing

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Esben Holm Hansen

UEG Presentation

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DISEASE BURDEN CATEGORIZATION AND MEDICATION USE IN POST-OPERATIVE CROHN'S DISEASE: A POPULATION-BASED COHORT STUDY

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DISEASE BURDEN CATEGORIZATION AND MEDICATION USE IN POST-OPERATIVE CROHN'S DISEASE: A POPULATION-BASED COHORT STUDY

Anja Poulsen 1,2, Mads Damsgaard Wewer 3, Julie Rasmussen 4, Hans Søe Jespersen 1, Elena Surnacheva 1, Dagmar Christiansen 4, Esben Holm Hansen 5, Rie Nordestgaard 3, Viviane Annabelle Lin 4, Kari Verlo 3, Nurcan Aydemir 4, Frederik Pachler 2, Pernille Dige Ovesen 2, Kristian Fuglsang 6, Christopher Filtenborg Brandt 6, Lars Tue Sørensen 1, Peter-Martin Krarup 1, Ismail Gögenur 4, Johan Burisch 3, Jakob Benedict Seidelin 2

Affiliations

1 Copenhagen University Hospital, Bispebjerg, København N, Denmark

2 Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark

3 Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark

4 Zealand University Hospital, Koege, Denmark

5 North Zealand University Hospital, Hilleroed, Denmark

6 University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark

Summary

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Abstract

Introduction

Resection rates for Crohn's disease (CD) have decreased over time, while re-resection rates have remained stable at about one-third in historic cohorts. Medical treatment has been shown to influence the course of the disease.

Aims & Methods

We aimed to assess the impact of disease burden categorization on medication use and risk factors. This cohort study encompassed all CD patients undergoing primary intestinal resection in Eastern Denmark from 2010 to 2020 (46% of the Danish population, n=2,730,000). We isolated all patients with five years follow up and divided them into three groups based on post-operative disease burden: high (one or more resections after the initial resection), intermediate (recurrence without need for resection), and low (no recurrence within five years). Disease recurrence was defined based on colonoscopy (SES-CD≥3, Rutgeerts score ≥i2), inflammation or stenosis on imaging (MRI, CTA, IUS), fecal calprotectin ≥ 250 mg/kg, starting corticosteroids or re-resection due to disease activity. Medication was classified by potency, with each patient assigned to only one category (no therapy<corticosteroids<immunomodulators<biologics). We used nonparametric statistics and the Kruskal-Wallis test to compare outcomes across groups.

Results

Primary resection was performed on 631 patients due to disease activity. Patients were categorized into burden groups: high burden (n=59), intermediate (n=287), and low (n=170). The median age at diagnosis was 28.2 years (range: 21.6-43.9), with no significant differences between the three disease burden groups (p=0.069). Age at primary resection differed across groups: 38 years (25-53) for high burden, 32 (24-45) for intermediate, and 36 (27-47) for low burden (p=0.019). Smoking rates were highest in the high burden group (47%) versus intermediate (37%) and low (27%) (p=0.010).
Pre-resection medical consumption was similar across the three burden groups (p=0.2). Postoperatively, the high burden group used more biologics (54%) compared to the low burden group (16%). Additionally, 57% of the low burden group remained recurrence-free and unmedicated for five years (Table 1). In the high burden group, no patients received prophylactic biologics, compared to 8% in the intermediate and low burden groups (p=0.001). Disease location varied: colon resections were most common in the high burden group (31%), and small bowel disease, including ileocecal resections, predominated in the low burden group (47%) (p<0.001). Strictures were more common in the intermediate and low burden groups, while luminal disease was mostly seen in the high-risk group (p=0.046) (Table 1)

Table 1. Medical characteristics and Montreal classification

	High N = 59	Intermediate N = 287	Low N = 170	p-value
After resection, biological therapy	32 (54%)	108 (38%)	28 (16%)	<0.001
After resection, immunomodulators	8 (14%)	106 (37%)	45 (26%)
After resection, no therapy	14 (24%)	56 (20%)	97 (57%)
L1 ileal	20 (34%)	119 (41%)	80 (47%)	<0.001
L2 colonic	18 (31%)	19 (6.6%)	12 (7.1%)
L3 ileocolonic	21 (36%)	149 (52%)	78 (46%)
B1 non-stricturing, non-penetrating	19 (32%)	43 (15%)	23 (14%)	0.046
B2 stricturing	32 (54%)	179 (62%)	108 (64%)
B3 penetrating	8 (14%)	64 (22%)	38 (22%)

Conclusion

High burden patients relied more on biologics, while half of the low burden patients stayed recurrence-free unmedicated for five years, suggesting tailored treatments could improve post-resection CD management.

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Histopathology IBD

Submission format

Abstract

Session

Finetuning treatment in IBD

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Patient with an early rectal cancer detected by FIT-screening

Leon M.G. Moons

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Michael Schumann

The bum: Haemorrhoids, fissure disease, urgency and incontinence

Tatenda Marunda

How to handle high risk conditions for gastric cancer

Judith Honing

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Antonino Granata

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Esben Holm Hansen