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JAK2 INHIBITION ATTENUATES PORTAL HYPERTENSION IN METABOLIC DYSFUNCTION-ASSOCIATED LIVER

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JAK2 INHIBITION ATTENUATES PORTAL HYPERTENSION IN METABOLIC DYSFUNCTION-ASSOCIATED LIVER

Yifei Liu 1, Shiyao Chen 1

Affiliations

1 Zhongshan Hospital, Fudan University, Shanghai, China

Summary

AI Generated

Ruxolitinib, a JAK2 inhibitor, significantly reduced portal pressure in a mouse model of MASLD-associated portal hypertension by modulating endothelial dysfunction and endothelial-to-mesenchymal transition.

In mice fed a high-fat diet for 12 weeks, ruxolitinib treatment (60 mg/kg by gavage every two days for 3 weeks) significantly reduced directly measured portal pressure and the spleen-to-body weight ratio.
Ruxolitinib treatment improved ALT, AST, and TC levels and decreased perisinusoidal and perivascular fibrosis on histopathological staining.
Electron microscopy revealed restoration of endothelial fenestration, and ruxolitinib downregulated endothelial damage markers, mesenchymal cell markers, and EndMT-related regulatory factors, indicating alleviation of endothelial dysfunction.
The study proposes that MASLD-associated portal hypertension may not depend solely on structural alterations like fibrosis but correlates with endothelial dysfunction, which JAK2 inhibition can target.
The findings position ruxolitinib as a promising candidate for clinical management of non-cirrhotic portal hypertension, particularly in MASLD-associated portal hypertension.

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Abstract

Introduction

Portal hypertension (PHT) most commonly due to cirrhosis, but non-cirrhotic portal hypertension (NCPH) related to metabolic dysfunction, specifically metabolic dysfunction-associated steatotic liver disease (MASLD), necessitates further clarification of its mechanisms and identification of therapeutic targets.

PHT may precede the development of hepatic fibrosis in MASLD, and even serve as a driving factor in the pathogenesis of MASLD. Consequently, metabolic dysfunction-associated PHT might not depend on structural alterations such as hepatic fibrosis or pseudolobule formation, but rather correlate with other factors such as endothelial dysfunction, which has been demonstrated to play a pivotal role in NCPH. Endothelial dysfunction encompasses endothelial injury and endothelial-to-mesenchymal transition (EndMT), the latter being a specific type of epithelial-to-mesenchymal transition (EMT). As reported, the JAK/STAT3 signaling pathway plays a pivotal role in the initiation and progression of EMT. Similarly, patients with NCPH induced by myeloproliferative neoplasms (MPN) often lack pathological features such as hepatic fibrosis or pseudolobule formation. The Janus kinase 2 (JAK2) V617F mutation is highly prevalent in MPN patients. Therefore, targeted inhibition of JAK2 serves as an effective therapeutic strategy for MPN.

Given the shared pathological features between MPN-associated portal hypertension and MASLD-associated portal hypertension, as well as the vital role of JAK2 in both disease, the application of JAK2 inhibitor holds significant therapeutic potential for metabolic dysfunction-associated portal hypertension.

Aims & Methods

This study aims to verify the therapeutic efficacy of JAK2 inhibition in attenuating MASLD-associated PHT, with particular focus on its modulation of EndMT. Mice were fed with a high-fat diet (HFD) diet for 12 weeks to induce MASLD-associated PHT and divided into two groups, the treatment group (Rux) and control (Ctr) group. Ruxolitinib (JAK2 inhibitor) was given as a suspension by gavage (60 mg/kg in 0.2 ml) every two days for 3 weeks, while controls received the same volume of saline, from week 10-12 of feeding. Portal pressure was measured, serological analysis and histopathological staining were performed. RT-PCR and Western Blot were conducted to measure EndMT-related genes expression.

Results

The treatment group (Rux) demonstrated a significant reduction in directly measured portal pressure, with concordant changes observed in the spleen-to-body weight ratio, which served as an indirect indicator of portal pressure. Concurrent improvement was noted in ALT, AST and TC. H&E, Masson and Sirius red staining showed decreased perisinusoidal and perivascular fibrosis in the Rux group. Electron microscopy revealed restoration of endothelial fenestration. Additionally, ruxolitinib treatment led to downregulation of endothelial damage markers, mesenchymal cell markers as well as EndMT-related regulatory factors, indicating an alleviation of EndMT and endothelial dysfunction.

Conclusion

The JAK2 inhibitor demonstrates therapeutic potential for MASLD-associated PHT through modulation of endothelial dysfunction and EndMT. These mechanistic insights position ruxolitinib as a promising candidate for clinical management of NCPH, particularly in the MASLD-associated PHT.

References

[1] European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. Diabetologia. 2024 Jun 13. [2] Song Z, Liu X, Zhang W, et al. Ruxolitinib suppresses liver fibrosis progression and accelerates fibrosis reversal via selectively targeting Janus kinase 1/2. Journal of Translational Medicine. 2022, 20(1): 157.
[3] Zhang XL, Zhang XY, Ge XQ, et al. Mangiferin prevents hepatocyte epithelial-mesenchymal transition in liver fibrosis via targeting HSP27-mediated JAK2/STAT3 and TGF-β1/Smad pathway. Phytotherapy Research. 2022, 36(11): 4167-4182.
[4] Jin W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition. Cells. 2020;9(1):217.
[5] Hammoutene A, Rautou PE. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. Journal of Hepatology. 2019, 70(6): 1278–1291.

Event

UEG Week Berlin 2025

Topics

Gut Microbiota Hepatobiliary Mechanisms & Personalised Medicine

Submission format

Abstract

Session

MASLD: Inflammatory mechanisms

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

UEG Presentation

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IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

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IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Alexandros Tsoposidis 1, Srdjan Kostic 1, Lars Lundell 2, Ville Wallenius 1, Hans Axelsson 1, Anders Thorell 3, Bengt Håkanson 3, Marcus Reuterwall Hansson 3

Affiliations

1 University of Gothenburg, Gothenburg, Sweden

2 Karolinska Institutet, Stockholm, Sweden

3 Karolinska Institutet, Stockholm, Sweden|||Ersta Hospital, Stockholm, Sweden

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Abstract

Introduction

The optimal surgical approach to reduce recurrence rates after laparoscopic repair of paraesophageal hernia (PEH) is yet to be defined. The crural repair is challenged by both axial and transverse-lateral tension, which may compromise durability. The aim of this double-blind randomized clinical trial was to investigate whether a left-sided diaphragmatic relaxing incision in addition to standard crural repair and fundoplication reduces anatomical recurrence rates at one year postoperatively.

Aims & Methods

This study was conducted at two high-volume Swedish centers—Ersta Hospital (Stockholm) and Sahlgrenska University Hospital (Gothenburg)—between August 2019 and August 2023. Adult patients undergoing surgery for PEH were randomized 1:1 to either standard crural repair with total (360°) fundoplication (control) or the same procedure with the addition of a left-sided diaphragmatic relaxing incision covered by synthetic mesh (intervention). Patients with prior hiatal surgery, ASA class IV or above, type I hernia, major esophageal motility disorders, or any contraindication to fundoplication were excluded. Blinding for patients and assessors was maintained throughout follow-up. Pre- and postoperative assessments included computed tomography (CT), symptom questionnaires (Dakkak dysphagia score, Gastrointestinal Symptom Rating Scale [GSRS]), and quality of life (QoL, RAND-36). The primary outcome was radiologically confirmed PEH recurrence at 12 months.

Results

Of 103 patients screened, 76 were randomized (38 per group). Baseline characteristics were well balanced. CT was completed in 72 patients (95%) at 12 months. The recurrence rate was 66% in the control group and 54% in the intervention group (p=0.313). Three patients in the intervention group had asymptomatic CT verified herniation at the site of the diaphragmatic incision. There were no differences in recurrence size distribution (<4 cm vs >4 cm) between groups. Postoperative symptom assessment revealed significant improvements in dysphagia, reflux, indigestion, and abdominal pain in both groups, without intergroup differences. Physical QoL (PCS) improved significantlywhereas mental QoL (MCS) remained unchanged. Two deaths occurred within 90 days postoperatively (1 per group), yielding a 90-day mortality of 2.6%. Other complications included mediastinal abscess (n=1, intervention group) and need for postoperative endoscopic dilatation (n=5 in total). Operation time tended to be longer in the intervention group (150 vs 133 min; p=ns).

	Crural repair alone	Crural repair with relaxing diaphragmatic incision	P value
Completed CT chest at 1 year	35/38	37/38
Radiological recurrence	23 (66%)	20 (54%)	.313
Recurrence<4cm	12 (34%)	11 (30%)	.522
Recurrence>4cm	11 (31%)	9 (24%)	.457

Table 1: Radiological recurrences 1 year after surgical repair of PEH

Conclusion

In this randomized, double-blind trial, the addition of a left-sided diaphragmatic relaxing incision to standard laparoscopic PEH repair did not improve anatomical recurrence rates, symptom relief or QoL at 12 months after surgery and should not be recommended for routine use. Alternative strategies to improve recurrence rates after PEH need to be explored in the future.

Event

UEG Week Berlin 2025

Topics

Neurogastroenterology & Motility Oesophagus

Submission format

Abstract

Session

Burning issues in GERD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

UEG Presentation

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The diagnosis

Bruce E. Sands 1

Affiliations

1 Icahn School of Medicine at Mount Sinai, New York, United States of America

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Primary Care

Session

When IBD and IBS experts collaborate for optimal diagnosis and treatment of IBD with IBS-like symptoms

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

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LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Maya Fischman 1, Michal Codish 2, Revital Barkan 3, Ian White 4, Nir Wasserberg 4, Keren M Rabinowitz 5, Tom Konikoff 5, Irit Avni-Biron 5, Hagar Banai Eran 5, Yifat Snir 5, Henit Yanai 3, Lihi Godny 4, Iris Dotan 4, Jacob E. Ollech 4

Affiliations

1 Rabin Medical Center, Petah Tikva, Israel|||Hebrew University of Jerusalem, Jerusalem, Israel

2 Tel Aviv University, Tel Aviv, Israel

3 Rabin Medical Center, Petah Tikva, Israel|||Tel Aviv University, Tel Aviv, Israel

4 Tel Aviv University, Tel Aviv, Israel|||Rabin Medical Center, Petah Tikva, Israel

5 Rabin Medical Center, Petah Tikva, Israel

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Abstract

Introduction

In patients with ulcerative colitis (UC), total proctocolectomy with restorative ileal pouch-anal anastomosis (IPAA) is a definitive surgical treatment for refractory disease or colorectal dysplasia. A short rectal cuff is typically retained and anastomosed to the pouch, and may become inflamed over time, a condition referred to as cuffitis. The clinical relevance of cuffitis remain unexplored. In this study, we aimed to characterize the long-term disease course associated with histologic cuffitis.

Aims & Methods

Patients with UC who underwent total proctocolectomy and IPAA were prospectively followed in a comprehensive pouch clinic at a tertiary referral center for patients with inflammatory bowel diseases (IBD). We included all patients who underwent at least one pouch endoscopy with paired pouch and cuff biopsies between 2017 and 2024. Cuffitis was defined as a NANCY Index histologic score of 3-4, and pouchitis was defined as histologic subscore of PDAI³2. Outcomes assessed included documented inflammatory pouch flares, defined by clinical evaluation; antibiotics used due to pouch inflammation; and initiation of biologics. Associations were evaluated using Poisson regression to estimate incidence rate ratios (IRRs) and Fisher’s exact test for categorical comparisons.

Results

A total of 116 patients underwent 250 pouch endoscopies during the study period. Average age of the cohort was 50.4 (±14.9) and 59% were females. Histologic pouchitis was detected in 80 (68.9%), and cuffitis in 76 (65.5%) patients. Most patients had extensive disease prior to IPAA (n=105, 90.5%) and indication for surgery was refractory UC (n=94, 81.0%). Concurrent pouchitis and cuffitis were identified in 54 (46.5%) patients. Patients with histologic-proven cuffitis had a significantly higher incidence rate of subsequent disease flares(IRR 4.39, 95% CI: 2.26-9.86, p<0.001) and required more antibiotic courses (IRR 1.94, 95% CI: 1.11-3.62, p=0.027) compared to those who never developed cuffitis. These associations remained significant after adjusting for the presence of histologic pouchitis. No significant difference was observed in the initiation of biologics (p=0.81). Among patients with at least two endoscopies during follow-up and isolated cuffitis at baseline (n=61), 6 patients with isolated cuffitis further developed new-onset pouchitis, while 15 patients with isolated pouchitis subsequently developed cuffitis. The remaining 40 patients (65.5%) maintained the same inflammatory pattern over time.

Conclusion

Histologic-proven cuffitis is independently associated with adverse long-term outcomes in patients post-IPAA, including flares and repeated antibiotic use, even in the absence of pouchitis. The persistence of inflammation in the retained rectal cuff, representing a remnant of the previously diseased colonic mucosa, raises mechanistic questions about its potential role in modulating inflammatory activity of the pouch. These findings emphasize the clinical importance of evaluating the rectal cuff in patients post-IPAA. Routine histologic assessment of the cuff should be incorporated into post IPAA surveillance, and interventional studies are warranted to determine whether targeted treatment of cuffitis can mitigate pouch related morbidity.

Disclosure

Jacob E Ollech: Has received grant support from Pfizer, consulting fees from Takeda, and
speaker fees from Abbvie, Janssen, Pfizer, Takeda, Novartis, and Bristol Myers Squibb.
Iris Dotan: consultation fee or honorarium from: Abbott, Abbvie, Athos, Arena, Altman
Research, Cambridge Healthcare, Celltrion, Celgene/BMS, Eli-Lilly, Ferring, Falk Pharma, Food
Industries Organization, Gilead, Galapagos, Iterative Scopes, Integra Holdings, Janssen,
Neopharm, Pfizer, Rafa laboratories, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda,
Wildbio. Grants: Altman Research, BMS, Pfizer

Event

UEG Week Berlin 2025

Topics

Colorectal Endoscopy Surgery IBD

Submission format

Abstract

Session

Lower GI: Surgical considerations

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Approaching the design of low prevalence diseases

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Approaching the design of low prevalence diseases

Federico Biagi 1

Affiliations

1 University of Pavia, Pavia, Italy

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Abstract

Event

UEG Week Berlin 2025

Topics

Mechanisms & Personalised Medicine Standards & Guidelines

Session

The art of making clinical research precise: Options for study design

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

How to boost wound healing in- and outside

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Not sure what you can access? Learn more about account types.

How to boost wound healing in- and outside

Ailsa L Hart 1

Affiliations

1 St Mark’s Hospital and Academic Institute, Harrow, United Kingdom

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Primary Care Surgery

Session

Disease primer: From inflammation to restoration - wound healing in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Who is at risk: Is it all about anticoagulants?

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

Who is at risk: Is it all about anticoagulants?

Franco Radaelli 1

Affiliations

1 Valduce Hospital, Como, Italy

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Abstract

Event

UEG Week Berlin 2025

Topics

Endoscopy Radiology & Imaging

Session

Crash course: Lower GI bleeding

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

IMPACT OF DIAPHRAGMATIC RELAXING INCISION ON RECURRENCE RATE AFTER PARAESOPHAGEAL HERNIA REPAIR; 1 YEAR RESULTS OF A DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL

Marcus Reuterwall Hansson

The diagnosis

Bruce E. Sands

LONG-TERM OUTCOMES OF CUFFITIS IN PATIENTS AFTER TOTAL PROCTOCOLECTOMY WITH ILEAL POUCH-ANAL ANASTOMOSIS DUE TO ULCERATIVE COLITIS

Ian White

Approaching the design of low prevalence diseases

Federico Biagi

How to boost wound healing in- and outside

Ailsa L Hart

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

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