Introduction

Semaglutide, a glucagon-like peptide-1 receptor analogue approved for treatment of type 2 diabetes (T2D) and overweight or obesity, is being investigated as a potential treatment for patients with metabolic dysfunction-associated steatohepatitis (MASH). Here, we present safety data from two phase 2 trials of subcutaneous semaglutide in patients with MASH with or without compensated cirrhosis.

Aims & Methods

This was a post-hoc analysis of two trials: NCT02970942 (320 patients with fibrosis stage F1–3 randomised 3:1 to once-daily semaglutide 0.1, 0.2 or 0.4 mg [n=80, 78 and 82] or placebo [n=80] for 72 weeks) and NCT03987451 (71 patients with compensated cirrhosis randomised 2:1 to once-weekly semaglutide 2.4 mg [n=47] or placebo [n=24] for 48 weeks). Patients received diet/lifestyle advice in both trials. Safety data were analysed descriptively.

Results

​In NCT02970942, 18 patients discontinued semaglutide due to adverse events (AEs), with a similar proportion of patients discontinuing in the semaglutide 0.4 mg (5%; 4/82) and placebo arms (5%; 4/80). In NCT03987451, three patients from the semaglutide arm (6.4%) discontinued due to AEs. In both trials, gastrointestinal (GI) disorders were the most common AEs with semaglutide (64–77% vs 33–45% with placebo); most GI AEs with semaglutide were non-serious and mild (55–71%) or moderate (22–36%). The proportion of patients with GI AEs with semaglutide in the MASH trials (63.8–76.9%) was similar to that seen in the weight management program STEP (63.5–82.8%), but higher than in the T2D development program SUSTAIN (34.4–52.0%).
There were no reported cases of acute pancreatitis. Overall, the proportion of patients with hepatic AEs (most frequently reported [in 0–3 patients per arm]: blood bilirubin increased, alanine transaminase increased, hepatic enzyme increased, international normalised ratio increased, transaminases increased, ascites) was 8–11% with semaglutide versus 4–14% with placebo. Few gallbladder-related AEs were reported. Four cholelithiasis events occurred in the semaglutide arms in the two trials; three were serious, of which two led to cholecystitis or cholangitis. All three serious events resolved with cholecystectomy. No cases of drug induced liver injury were reported. Throughout the trials (up to 72 weeks), three patients in the semaglutide group reported malignant neoplasms (breast cancer, endometrial adenocarcinoma and peripheral T-cell lymphoma) vs none with placebo; all events were judged as unlikely to be related to semaglutide.

Conclusion

Data from two phase 2 trials indicate that semaglutide is generally well tolerated in patients with MASH, including those with compensated cirrhosis. No new safety concerns were identified, and the safety profile was similar to that in patients with T2D and overweight/obesity. Data from the ongoing phase 3 trial (NCT04822181) will provide further knowledge about the safety of semaglutide in patients with MASH.

Disclosure

Funding: Novo Nordisk A/S.

Medical writing: Diana Marouco, PhD, of OPEN Health Communications, provided medical writing support, which was funded by Novo Nordisk A/S in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).
Lise Lotte Gluud is scientific advisor and consultant for Alexion, Becton Dickinson, Gilead, Norgine, Novo Nordisk, Pfizer, Sobi and Vingmed.
Philip N Newsome has received grants from Boehringer Ingelheim and Novo Nordisk and is a consultant for Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Glaxo SmithKline, Intercept Pharmaceuticals, Novo Nordisk, Pfizer, Poxel Pharmaceuticals, Sagimet Terns and Theratechnologies.
Stephen A. Harrison is scientific advisor and consultant for Novo Nordisk.
Mette Skalshøi Kjær is a full-time employee and shareholder of Novo Nordisk A/S.
Maximilian Kurt Jara, Amine Lotfi, Karina Phonekeo and Mads Sundby Palle are full-time employees of Novo Nordisk A/S.
Encore statement: This abstract was also presented at the European Association for the Study of the Liver (EASL) Congress, 21–24 June 2023 in Milan, Italy.

Introduction

Increased intestinal permeability, or leaky gut, is a condition where the gut's epithelial barrier is compromised, allowing bacteria and toxins to enter the blood stream. In liver cirrhosis, this can exacerbate liver damage and accelerate disease progression by perpetuating inflammation and immune system activation. Accurate assessment of this dysfunction is critical to the management of cirrhotic patients, but traditional methods such as serum markers and indirect assays often lack specificity and sensitivity.
Confocal laser endomicroscopy (CLE) is an advanced imaging technique that provides real-time, high-resolution visualisation of the gastrointestinal tract at the cellular and subcellular levels. CLE is used to diagnose leaky gut by directly observing disruptions in the intestinal mucosa. It integrates a confocal microscope within an endoscope, enabling in vivo histology-like imaging during routine endoscopic examinations.

Aims & Methods

We aimed to use confocal laser microendoscopy (CLE) in the diagnosis of intestinal barrier dysfunction by direct observation of the intestinal mucosa, in patients with liver cirrhosis. CLE (Cellvizio, Mauna Kea Technologies) was performed in the second part of the duodenum following intravenous administration of 2.5 – 5 mg of fluorescein in 58 patients with liver cirrhosis of various aetiologies. These patients were undergoing routine endoscopic surveillance or therapeutic intervention for oesophageal varices. The study cohort consisted of 39 men (61.9%) and 19 women (30.2%), with a mean age of 53.9 ± 14.0 years. We collected and analysed the most recent results of hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and fibrosis index for liver fibrosis (Fib-4). A Watson score of 1 indicates normal barrier function, while a Watson score of 2 indicates impaired barrier function. Data are given as mean± standard deviation, statistical analysis included Chi-square tests and Student’s t-tests, with a significance level set at p<0.05. NS=not significant.

Results

We observed a gradation of intestinal barrier dysfunction that correlated with the severity of liver cirrhosis. Specifically, of the 35 patients with Child-Pugh A cirrhosis, 18 (51.4%) had a Watson score of 2. In the group of 14 patients with Child-Pugh B cirrhosis, 9 (64.3%) had a Watson score of 2 and of the 9 patients with Child-Pugh C cirrhosis, 8 (88.9%) had a Watson score of 2, further underscoring the trend of increasing intestinal barrier dysfunction with increasing liver disease severity (p<0.05). In contrast, no significant differences in hepatic venous pressure gradient (HVPG) were observed between patients with Watson score 1 (16.8 ± 6.2 mmHg) and Watson score 2 (17.2 ± 6.2 mmHg, p NS). Similarly, liver stiffness measurements (LSM) showed no statistical difference between patients with Watson score 1 (39.0+/-23.7 kPa) and those with score 2 (40.2 ± 22.9 kPa) (p NS)=. Similarly, Fib-4 was 4.5 +/-3.1 in patients with Watson score 1 and 5.7+/-3.6 in patients with Watson 2 (p NS).

Conclusion

The findings suggest an association between the severity of liver cirrhosis and impaired intestinal barrier function as assessed by CLE. This impairment does not correlate with changes in haemodynamic parameters or liver fibrosis. The CLE promises to provide accurate and immediate diagnostic data and to improve our understanding of the pathophysiological changes in the gut associated with liver cirrhosis. Further research is needed to explore the mechanisms linking the severity of cirrhosis to intestinal barrier dysfunction and its clinical implications.

Disclosure

No conflict of interest to declare

Introduction

Steatotic liver disease (SLD) encompasses a spectrum of conditions, including metabolic dysfunction-associated SLD (MASLD), alcohol-related liver disease (ALD), and the overlapping category of MetALD. SLD affects more than a third of adults globally, but the majority remain undiagnosed, partially due to its lack of symptoms and limited awareness among patients and physicians. Adults undergoing screening colonoscopy, typically aged ≥50 years, represent a key population for targeted SLD detection, as they have a higher prevalence of cardiometabolic risk factors and is already engaged with preventive healthcare.

Aims & Methods

We examined 610 consecutive individuals aged ≥50 years with no known history of chronic liver disease who were referred for a colonoscopy for colorectal cancer screening. The protocol included sonographic assessment of liver steatosis and point shear wave elastography (pSWE) for liver fibrosis quantification, anthropometric measurements, biochemistry, medical history and alcohol intake evaluation. From the collected data, non-invasive fibrosis scores were calculated and used for aetiological and risk stratification.

Results

A total of 543 patients were included in the final analysis, after excluding patients with an invalid pSWE measurement (5.3%, n=29) and then excluding patients with incomplete results (n=38). The median age was 64 years (IQR 57-70) and 54.0% were male. The median BMI was 28.7 kg/m² (IQR 25.8–31.4) in males and 28.3 kg/m² (IQR 24.2-31.5) in females. SLD was identified in 63.4 % (n=344) of participants. Elevated liver stiffness (pSWE ≥ 1.30 m/s) was found in 26.9 % (n=146), and 4.8% (n=26) had values ≥1.70 m/s, suggestive of compensated advanced chronic liver disease. Among patients with pSWE ≥ 1.30 m/s, MASLD was the predominant aetiology (69.9%, n=102), followed by MetALD (15.8%, n=23), ALD (1.4%, n=2), cryptogenic (11.6%, n=17) and other etiologies (1.4%, n=2). Preselection using EASL-EASD-EASO criteria (i.e. presence of type 2 diabetes or central obesity plus ≥1 cardiometabolic risk factor and elevated liver enzymes) would have detected 365 at-risk individuals (67.2% of the cohort) of whom 55.9% (n=204) had a FIB-4 index ≥1.30. This approach would have identified only 30.4% (n=38) of all the patients with MASLD/MetALD with elevated liver stiffness (n=125).

Conclusion

Opportunistic screening for SLD in patients undergoing screening colonoscopy could be a useful strategy for detecting asymptomatic and potentially progressive liver disease. This approach identified a high prevalence of SLD (63.4%) and elevated liver stiffness (26.9%) in this population, primarily due to MASLD and MetALD. The integration of ultrasound and elastography added minimal burden to the existing workflow while enabling early risk stratification without the need for additional patient visits or referrals.

References

1 Tacke F, Horn P, Wong VWS, Ratziu V, Bugianesi E, Francque S, et al. EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology [Internet]. 2024 Jun 7;81(3):492–542.
2 Lazarus JV, Miralles-Sanchez JE, Agirre-Garrido L, Brachowicz N, Nicolàs A, Armenta A, et al. A call to action to address the steatotic liver disease public health threat in Barcelona. The Lancet Regional Health - Europe [Internet]. 2025 Mar 22;52:101272.
3 Barr RG, Wilson SR, Rubens D, Garcia-Tsao G, Ferraioli G. Update to the Society of Radiologists in Ultrasound Liver Elastography Consensus Statement. Radiology [Internet]. 2020 Jun 9;296(2):263–74.

Introduction

With about 40% of adults infected with Helicobacter pylori (H. pylori), China has the highest number of gastric cancer (GC) cases worldwide.¹ Household transmission is the primary route for H. pylori infection,² and family-based testing and treatment has been proposed to mitigate GC cancer risk and prevent transmission.^1,3,4 A household-based transmission model for H. pylori would enhance understanding of H. pylori dynamics and inform intervention strategies. However, few models⁵ have been developed for H. pylori, and none incorporates household transmission.

Aims & Methods

We developed an agent-based household transmission model for H. pylori in China to study transmission patterns from 1990 to 2021. Building on our previous modeling framework,⁶ the model includes demographic and transmission components. The demographic simulation captures births, deaths, marriages, and mobility among youth, couples, and the elderly. Mobility parameters were calibrated using joint distributions of household size and generation from Chinese censuses of 1990, 2000, 2010, and 2020, allowing realistic household dynamics in China. In the transmission simulation, household and community transmissions were modeled using a susceptible-infected structure, applying density-dependent transmission within households and frequency-dependent transmission in the community. Contact rates, defined as the number of contacts adequate for transmission by an individual per year, were allowed to vary over time, and were dependent on the susceptible individual’s age. Contact rate variation was modeled by adjusting base rates with age- and year-specific multipliers, each following a continuously decreasing function. Simulations began in 1900, with the first 90 years as a burn-in period. Transmission parameters were calibrated and validated using data from our meta-analyses and a large national family-based survey from China in 2021⁷.

Results

The model aligned well with calibration targets. Key parameters and calibration results are summarized in the Table. Consistent with observed data, larger households had higher infection rates than smaller households. Three-generation households were more likely to have infected members than one- or two-generation households. Model calibration showed best fit when the within-household contact rate (0.2) was higher than the community rate (0.1), and when most infections occurred before age 20. Validation confirmed model accuracy: children’s infection probabilities were 31% with both parents infected, 21% with one infected parent, and 9% with neither. Our model found that family clustering became more pronounced in recent years with lower prevalence compared to earlier periods with higher prevalence.

Table. Calibration and validation results for the transmission model

Conclusion

We developed a novel agent-based model simulating community and household transmission of H. pylori. Our results confirm that household transmission is the primary infection route, and that childhood is the predominant period of acquisition. Notably, family clustering becomes more prominent in low-prevalence contexts. This model provides a valuable tool for evaluating various control strategies and offers insights difficult to obtain in real-world data. Future extensions could incorporate antibiotic resistance dynamics and adapt the model to other country contexts.

References

1. Ding, S.-Z. et al. Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition). Gut 71, 238–253 (2022).
2. Malfertheiner, P. et al. Helicobacter pylori infection. Nat. Rev. Dis. Primer 9, 1–24 (2023).
3. Chey, W. D. et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Off. J. Am. Coll. Gastroenterol. ACG 119, 1730 (2024).
4. Shah, S. C., Wang, A. Y., Wallace, M. B. & Hwang, J. H. AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review. Gastroenterology 168, 405-416.e1 (2025).
5. Rupnow, M. F. T., Shachter, R. D., Owens, D. K. & Parsonnet, J. A Dynamic Transmission Model for Predicting Trends in Helicobacter pylori and Associated Diseases in the United States. Emerg. Infect. Dis. 6, 228–237 (2000).
6. Blok, D. J. et al. The long-term impact of the Leprosy Post-Exposure Prophylaxis (LPEP) program on leprosy incidence: A modelling study. PLoS Negl. Trop. Dis. 15, e0009279 (2021).
7. Zhou, X.-Z. et al. Large-scale, national, family-based epidemiological study on Helicobacter pylori infection in China: the time to change practice for related disease prevention. Gut 72, 855–869 (2023).B1

Introduction

Recurrence of primary sclerosing cholangitis (rPSC) is a common long-term complication after liver transplantation (LT), which affect graft survival and overall patient survival. There are several lines of evidence indicating that dysregulation of the microbiome and intestinal barrier dysfunction are key etiologic factors in the pathogenesis of PSC.

Aims & Methods

The aim of this cross-sectional study was to evaluate serological markers of intestinal barrier permeability in patients with PSC after LT and in control group, to determine potential biomarkers for rPSC. The control group consisted of LT recipients for alcohol-related liver disease and/or hepatocellular carcinoma. The rPSC was assessed by MRCP and/or biopsies, all patients underwent colonoscopy. Serum levels of iFABP, Zonulin and Reg3a were evaluated. Non-parametric tests were used to for initial assessment. We further built generalized linear models for the prediction of PSC diagnosis independent of recurrence (Model_1), for the prediction of non-rPSC (Model_2) and for the prediction of rPSC (Model_3) using all three permeability markers, BMI and faecal calprotectin as predictors.

Results

A total of 113 patients were included in the study after LT for PSC and 69 controls. The clinical characteristics of the study participants are listed in Table 1. No significant difference in median of concentrations of Reg3a was found between the PSC group and control group (p=0.01). Interestingly, medians of concentrations of iFABP (p<0.01) and (p<0.0001) Zonulin were significantly higher in the control group in comparison with PSC group. The ROC AUC for Model_1 for prediction of PSC diagnosis per se was 0.79. The increased probability of PSC occurrence was associated with higher Reg3a serum concentration, while a negative relationship was found between the probability of PSC occurrence and BMI, zonulin and iFABP. Model_2, prediction of PSC without recurrence (non-rPSC), achieved slightly better performance, ROC AUC = 0.83, but the predictors and their coefficients and OR were close to Model_1. The ROC AUC for Model_3 predicting rPSC was 0.73. In contrast to previous models, BMI, Reg3A and iFABP were not significantly associated with rPSC, while both higher serum concentrations of zonulin and calprotectin increased the probability of PSC recurrence.

Table 1. - Cohort characteristics

Conclusion

Recurrence of PSC was positively associated with the intestinal permeability marker zonulin and the inflammatory marker calprotectin, while it was independent of BMI, iFABP and Reg3a.

Introduction

Lymphangiectasia and lymphangiectic cysts result from dilated intestinal lacteals due to disordered drainage. This can result in leakage of lymph into the lumen with resultant hypoproteinaemia, hypogammaglobulinaemia, hypoalbuminaemia and a lymphopenia (1,2). This is most clinically apparent in those with widespread severe change, such as congenitally anomalous drainage or secondary causes including, infections, lymphoma/malignancy, inflammation or radiotherapy (1,3,4). This can result in malabsorption or widespread failure of lymphatic drainage.
It is unclear whether subtle incidental lymphangiectasia without clinical malabsorption are significant. Subtle, incidentally noted changes including scattered pinpoint white spots, prominent villi with white tips and small focal macules or nodules (5) are an increasingly common finding. With increased use of high-definition capsule technology, more subtle changes are increasingly recognised. Older studies show these are common, with follow up and fat absorption studies concluding that incidentally noted dilated lacteals, without clinical malabsorption likely did not require follow up (5–7).

Aims & Methods

We aim to assess whether the incidental, and “clinically insignificant”, lymphangiectasia seen on capsule endoscopy are associated with changes in protein, albumin, cholesterol, triglyceride, calcium or lymphocyte levels. The hypothesis being that more subtle lymphatic anomaly will result in a more subtle biochemical picture.
Values are stated as means (+/- SD) with P values calculated using two tailed t-test or Chi square, <0.05 taken as significant.

Results

21 patients with lymphangiectasia noted to be the only, or main, finding on capsule endoscopy were retrospectively reviewed. 21 age and gender matched controls (61.9% male, aged 52 (+/-15) years) with normal capsule and colonoscopies were extracted for comparison. Comorbidities and blood results were recorded for each.
Two patients with clinically significant widespread lymphatic changes secondary to systemic disease (disseminated mycobacterial infection and end stage cirrhosis both with lymphatic obstruction) were excluded. The remaining patients had either incidental scattered white tipped villi, discrete nodules/polyps of dilated white villi, or discrete chylous cysts (or a combination of these).

Conclusion

This study would suggest that those with lymphangiectasia have lower protein, albumin, calcium, cholesterol, and triglyceride levels (protein, albumin and triglycerides reaching statistical significance). There is a paucity of recent research in this field and the historical assumption that incidentally noted lymphangiectasia are meaningless may not be entirely accurate. Correlation does not equal causation as these markers are dependent on a huge number of factors. This is a small patient group, and a larger study would be required to further explore this. Selectively blocking small bowel lymphatics may represent a potential therapeutic target and further research in this field could have a range of clinical implications.

References

1. Freeman HJ, Nimmo M. Intestinal lymphangiectasia in adults. World J Gastrointest Oncol. 2011;3(2):19.
2. Hu D, Cui X, Ren W, Zhang J, Guan X, Jiang X. A case of primary intestinal lymphangiectasia with non-Hodgkin lymphoma. BMC Gastroenterol. 2021 Dec;21(1):461.
3. Iwamuro M, Tanaka T, Kanzaki H, Kawano S, Kawahara Y, Iwasaki Y, et al. Deterioration of duodenal lymphangiectasia after radiotherapy for gastric MALT lymphoma. ecancermedicalscience [Internet]. 2017 Jul 11 [cited 2023 Apr 1];11. Available from: http://www.ecancer.org/journal/11/full/752-deterioration-of-duodenal-lymphangiectasia-after-radiotherapy-for-gastric-malt-lymphoma.php
4. Taveira F, Magalh�es JP, Brito D. Duodenal Lymphangiectasias - The first sign of Pancreatic Adenocarcinoma. Rev Esp Enfermedades Dig [Internet]. 2021 [cited 2023 Apr 1]; Available from: https://online.reed.es/fichaArticulo.aspx?iarf=732799150340-589162820258
5. Kim J, Bak Y, Kim J, Seol S, Shin B, Kim H. Clinical significance of duodenal lymphangiectasia incidentally found during routine upper gastrointestinal endoscopy. Endoscopy. 2009 Jun;41(06):510–5.
6. Patel AS, DeRidder PH. Endoscopic appearance and significance of functional lymphangiectasia of the duodenal mucosa. Gastrointest Endosc. 1990 Jul;36(4):376–8.
7. Barnes RE, DeRidder PH. Fat absorption in patients with functional intestinal lymphangiectasia and lymphangiectic cysts. Am J Gastroenterol. 1993 Jun;88(6):887–90.