Introduction

In Nonalcoholic steatohepatitis (NASH), several pathogenetic mechanisms occur as explained by the “multiple hit pathogenesis”. However, the characteristic inflammation of NASH is orchestrated by the innate immunity, since Kupffer cells are triggered by PAMPs and DAMPs, and recruit monocytes (Mo), which repopulate the liver with new macrophages, perpetuating inflammation.
The recent promising field of immunometabolism showed that myeloid cells undergo a metabolic reprogramming to sustain the pro-inflammatory activity, suggesting novel immunosuppressive approaches by targeting cellular metabolism. However, immune cell bioenergetic alterations in chronic diseases such as NASH, are substantially unexplored.

Aims & Methods

Here, we questioned whether circulating Mo in NASH presented immunometabolic alterations. 20 NASH patients (histologically determined) and 10 healthy controls were enrolled for isolation of circulating CD14+ Mo from peripheral blood. Mo were used for analysis of bioenergetics and mitochondrial function, and RNA/protein isolation. To do this, glycolysis and mitochondrial respiration (MR) were quantified with extracellular acidification rate and oxygen consumption rate, respectively, by using a Seahorse HS Mini analyser (Agilent). Respiratory chain (RC) complexes enzymatic activities and H₂O₂ production rate were analysed. In a second step, the effect of succinate dehydrogenase (SDH) inhibition was investigated in vitro by exposing patient Mo to dimethyl malonate (DMM), and in vivo by using a preclinical model of NASH. In particular, wild-type (C57BL/6) mice were fed with high-fat and high-cholesterol (HF-HC) diet for 8 weeks. From week 6 to week 8 mice were i.p. injected with DMM (160 mg/kg), or vehicle (PBS) every second day.

Results

NASH Mo presented a peculiar bioenergetic profile characterized by a significant increase of both glycolysis and MR compared to controls, with a preponderant change of glycolysis. Basal and maximal respirations were higher in NASH Mo, although this resulted not only in more ATP production, but also in a very high proton leak. In accordance with this, we found that NASH Mo showed a higher enzymatic activity of RC complex I and complex II. However, using pyruvate/malate and succinate as substrates we observed that complex I and II activities produced high levels of H₂O₂ with consequent mitochondrial oxidative stress. Taken together these results highlighted that Mo in NASH have a bioenergetic reprogramming with increase of glycolysis and mitochondrial dysfunction. The mRNA expression of 78 targets, included in the PrimePCR^TM array “mitochondria energy metabolism plus”, showed the significant down-regulation of 7 genes, while 32 genes resulted up-regulated. Most of these genes encoded for RC complex subunits, and in particular, 3 out of 4 SDH subunits resulted more expressed. SDH is an enzyme complex also known as RC complex II, and its role in driving the metabolic rewiring of macrophages has been recently demonstrated. Therefore, considering the higher activity and expression of RC complexes, and in particular the SDH, we tried to expose NASH Mo to DMM, a SDH inhibitor with demonstrated immunomodulatory properties. Interestingly, DMM normalized glycolysis and MR levels, abrogating Il-1β and TNF-α expression. Moreover, HF-HC fed mice were treated with DMM, improving steatohepatitis in terms of liver injury, steatosis and inflammation. The macrophage amount in the liver was reduced and the expression of M2 markers such as arginase1 and CD163 was partially restored by DMM.

Conclusion

Mo immunometabolism might be targeted in NASH.

Introduction

The Percutaneous Endoscopic Gastrostomy (PEG) tube is used to provide enteral nutrition when oral intake is not adequate.
Regular follow-up of PEG patients is essential to detect complications and clarify doubts. A partnership protocol was developed with ACES Lisboa Central (ACESLC) and Loures/Odivelas (ACESLO) to improve continuity of care.

Results & Findings

We analyzed data from PEG patients followed between 2023 and 2024. Inclusion criteria for referral to ACES included:
• Clinical stabilization;
• Absence of PEG-related complications requiring hospital admission;
• Willingness and ability of the patient/caregiver to participate actively in care.
Monitoring of the protocol was based on quarterly evaluation of five performance indicators:
1st: Percentage of patients referred to ACES, out of the total seen in PEG review consultations;
2nd: Percentage of referred patients who returned to hospital before the expected date due to complications;
3rd: Percentage of cases in which complete referral documentation, as per protocol, was sent to ACES;
4th: Percentage of cases with confirmation that ACES sent back all required clinical data;
5th: Percentage of compliance with scheduled PEG follow-up appointments at ACESLO.

Summary & Discussion

The 1st indicator shows low referral rates in both years, mainly due to out-of-area institutionalization, clinical worsening, or death.
The 2nd indicator indicates fewer unplanned hospital readmissions among referred patients; when they occurred, complications were the cause.
Results show fewer complications and emergency visits, reflecting the benefit of close ACES collaboration.
The 3rd indicator reflects 100% compliance in sending referral documentation.
The 4th indicator showed gaps in home visit records in 2023, improved in 2024 through better coordination.
One challenge was the mismatch between designated ACES nurses and those conducting home visits, which required articulation with family health teams (USF).
The 5th indicator confirms overall adherence to scheduled PEG reviews.

Conclusion

The protocol streamlined follow-up for PEG patients.
In 2024, a previous limitation was overcome, allowing referrals of institutionalized patients within the protocol’s coverage.
As a pioneering project, we aim to share these findings to support protocol expansion to other units.

References

Kurion, M., Andrews, R., Tattersall, R., McAlindon, M., Wong, E., Johnston, A., Hoeroldt, B., Dear, K. & Sanders, D. (2017). Gastrostomies preserve but do not increase quality of life for patients and caregivers. Clinical Gastroenterology and Hepatology. 15, 1047-1054.
Lee, C.,Kang, H., Lim, Y., Lee, J., Koh, M., Lee, J., Yang, C. & Kim, J. (2013). Comparison of complications between endoscopic and percutaneous replacement of percutaneous endoscopic gastrostomy tubes. JKoren Medical Sciences. 28, 1781-1787.
Lucendo, A. J. & Friginal-Ruiz, A. B. (2014). Percutaneous endoscopic gastrostomy: An update on its indications, management, complications, and care. Revista Española de Enfermedades Digestivas. 106(8), 529-539.

Introduction

In recent years, the detection of Branch Duct Intraductal Papillary Mucinous Neoplasms (BD-IPMN) has increased. The Association of Pancreatology (IAP) approved specific guidelines for their management in Fukuoka in 2017. The rates of malignant degeneration of these lesions remain unclear, raising concerns about the cost-effectiveness of the suggested surveillance strategies.

Aims & Methods

This study aimed to identify the rates of BD-IPMN malignant degeneration and their associated risk factors to propose a new, more cost-effective surveillance strategy. In this multicentric retrospective observational study, clinical and histopathological data of patients with IPMN were collected by four tertiary centers in Northern Italy. Multivariate Cox regression identified factors associated with a higher risk of malignant degeneration. A segmentation analysis aimed to define new dimensional cut-offs for better risk stratification. Demographic and anamnestic data relating to the patient (age, gender, comorbidities based on the Age-Adjusted Charlson Comorbidity-Index (ACCI), imaging, endoscopic examinations, and surgical interventions), to IPMN (presence of Worrisome Features (WF) and High-Risk Stigmata (HRS) as defined by IAP), and surveillance costs were collected. Malignant degeneration was defined as the presence of high-grade dysplasia or invasive neoplasia.

Results

The study enrolled 333 patients, with a total of 1400 visits and a median follow-up of 4 years. IPMN developed malignant degeneration in 3.3% of cases. Cancer risk factors included the presence of HRS (HR 4.4, 95%CI 1.1-17.8, p = 0.04), of at least two WFs (HR 5.8, 95%CI 1.5-22.4, p = 0.01), and cyst size (HR 2.0, 95%CI 1.3-3.0, p < 0.001). The latter discriminated this risk (AUC 0.91, 95%CI 0.84-0.97), and two new cut-offs of 1.5 and 3.0 cm identified three dimensional categories with significantly different neoplastic potential (OR 6.6, 95%CI 1.7-25.4, p = 0.007, OR 9.8, 95%CI 1.1-89.7, p = 0.04). Based on this, we proposed a new surveillance strategy that maintained diagnostic accuracy while reducing the cost per patient for a 3-year follow-up from 670.01 (407.33-1130.32) to 587.01 (347.10-930.28) euro, resulting in a total savings of 11% (p = 0.001).

Conclusion

IPMN malignant degeneration was infrequent. The presence of at least one WF, currently a cornerstone of guideline recommendations, did not independently associate with neoplastic risk, unlike HRS and the presence of at least two WFs. Implementing a follow-up strategy based on operatively identified dimensions (1.5 and 3 cm) could potentially enhance the cost-effectiveness of the 2017 Fukuoka IAP guidelines.