Introduction

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease in recent years. However, medications to improve MAFLD has no standard. Several potential agents have been widely investigated for the treatment of MAFLD. Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, has been reported to improve dyslipidemia. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) is an oral antidiabetes drug that promotes glucose excretion into the urine. These medications have potential therapeutic effects on MAFLD.

Aims & Methods

This retrospective study aimed to evaluate the effects of long-term administration of pemafibrate plus SGLT2i in patients with dyslipidemia and type 2 diabetes complicated by MAFLD. Transient elastography (FiboScan; Echosens, Paris, France) was used for liver stiffness measurement (LSM) and assessment of the controlled attenuation parameter (CAP). In total, 594 patients with dyslipidemia and type 2 diabetes complicated by MAFLD started pemafibrate plus SGLT2i treatment between 2019 and 2020 at our hospital. Pre- and post-treatment transient elastography data were compared.

Results

Following 3 years of pemafibrate plus SGLT2i treatment, the median LSM significantly decreased from 10.1 kPa to 6.4 kPa (P < 0.001) and the median CAP significantly decreased from 321 dB/m to 219 dB/m (P < 0.001), in spite of no significant reductions of the studied patients’ weight. Moreover, serum parameters, including hemoglobin A1c, alanine aminotransferase, and gamma-glutamyl transferase, significantly decreased over the study period.

Conclusion

The findings of our study confirm that long-term administration of pemafibrate plus SGLT2i can improve hepatic fibrosis by ameliorating hepatic steatosis and inflammation in patients with dyslipidemia and type 2 diabetes complicated by MAFLD.

References

Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008; 48(5): 835-847.
Yamashita S, Masuda D, Matsuzawa Y. Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases. J Atheroscler Thromb. 2019; 26(5): 389-402.
Mantovani A, Petracca G, Csermely A, et al. Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Metabolites. 2020; 11(1): 22.
Murakami K, Sasaki Y, Asahiyama M, et al. Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. Cells. 2022;11(4):720.

Introduction

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders characterized by alterations of acute relapses and remission. The past decades have brought substantial advances in the pharmacological management of IBD by a wide range of medicines. However, the sustained efficacy of the currently available anti-inflammatory therapies is still far from optimal. Therefore, the development of novel therapies represents a major unmet clinical need in this field. Recently, the enrichment of the coagulation pathway genes and among these, Plasminogen activator inhibitor 1 (PAI-1) was described in IBD, whereas PAI-1 emerged as a link between the epithelium and inflammation. Moreover, the genetic deletion of PAI-1 prevented the severity of experimental colitis in mice.

Aims & Methods

Based on these, we aimed to develop and test novel PAI-1 inhibitors for the treatment of IBD.
The novel, amino acid-based PAI-1 inhibitor, LDN-071 was synthesized by the A³SMO^® platform. The inhibitory potential and cytotoxicity effects of the peptide were determined by in vitro assays. Acute and chronic colitis was induced in mice with DSS and 10 mg/bwkg LDN-071 was administered per os. The changes of body weight, spleen weight, and colon length were measured. Haematoxylin eosin (HE) and Periodic acid-Schiff (PAS) staining were performed for histology. ELISA and qRT-PCR measurements were applied to analyze the cytokine expressions. Hydroxyproline assay was used to quantify the mucosal collagen deposition. In vivo, the toxicity of LDN-071 was determined in mice. Human colon organoid and fibroblast (FB) cell cultures were generated from IBD patients and the effects of LDN-071 were observed.

Results

LDN-071 significantly inhibited PAI-1 in vitro without decreasing the cell viability in a concentration range of 1µM-1mM. In the acute mice model, the administration of 10 mg/bwkg LDN-071 in the DSS-treated mice prevented the body weight loss, the development of bloody diarrhea, the decrease of colon length, and the increase of the spleen weight, which were displayed by the DSS+vehicle-treated animals. The histological analysis of the colon revealed that DSS treatment induced severe transmural inflammation, ulceration, loss of crypt structures, and goblet cell depletion. Importantly, all these parameters were significantly ameliorated by the administration of 10 mg/bwkg LDN-071 in the acute and chronic models as well. Additionally, mucosal gene and protein expressions of TNF-α, IL-1β, and IL-6 were significantly decreased by PAI-1 inhibition in the acute phase. Besides, the LDN-071 treatment significantly reduced the inflammation, epithelial erosion, and fibrosis caused by chronic administration of DSS. However, the collagen deposition was significantly lower in the PAI-1-inhibited DSS mice. Importantly, no signs of toxicity were observed in mice exposed to 100 mg/bwkg LDN-071 for 7 days. In our in vitro models, the PAI-1 inhibition reduced the protein level and gene expression of pro-inflammatory cytokines in human colon organoid of IBD patient. Moreover, the gene expression of fibrosis-related genes significantly decreased after the LDN-071 treatment in IBD patients-derived human FB cell culture.

Conclusion

Our results showed that LDN-071, a novel amino acid-based inhibitor of PAI-1, significantly ameliorated the severity of acute and chronic colitis in mice. However, the LDN-071 reduced the expression of inflammation- and fibrosis-related genes and proteins in vitro human models. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.

Disclosure

LDN-071 PAI-1 inhibitor is owned by Ladon Therapeutics Ltd.

Clinical Case Summary

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by remitting and relapsing patterns, necessitating multifaceted therapeutic interventions, among which mesalazine, or 5-aminosalicylic acid (5-ASA), is prominently utilized. Despite its typically favorable tolerability profile, mesalazine may occasionally precipitate severe adverse events, such as myocarditis.
Case presentation: A 46-year-old male recently diagnosed with UC presented with a moderate UC flare-up and was initiated on 5-ASA therapy upon admission.
Within a span of two days following initiation of oral therapy, he developed acute chest pain, palpitations, dyspnea, and desaturation, necessitating intensive care due to cardiogenic shock.
Paraclinical assessments revealed elevated troponin levels, along with electrocardiographic and echocardiographic abnormalities, including left ventricular dysfunction and reduced ejection fraction.
Discontinuation of mesalazine resulted in symptom improvement and reduction of cardiac markers. Subsequent evaluations demonstrated a recovery in cardiac function, establishing a causal relationship between myocarditis and the administration of 5-ASA. Consequently, a therapeutic switch to mercaptopurine was instituted.
Conclusion: This case underscores the infrequent yet significant hazard of mesalazine-triggered myocarditis, emphasizing the critical necessity for vigilant patient monitoring during this therapy and prompt consideration of alternative therapeutic options in the presence of severe cardiac complications.

Introduction

Accepted oncological principles advise enbloc, R0, excision of cancer to provide a cure. In Barrett’s neoplasia, this includes T1a and T1b disease, where histology is favorable. While treatment options include endoscopic mucosal resection (EMR) and submucosal endoscopic dissection (ESD), a mechanism for appropriate technique selection has not been described.

Aims & Methods

We conducted a prospective observational study to evaluate the performance of a selective resection algorithm for Barrett’s neoplasia (SRAB). To achieve an enbloc resection, ESD was selected if there was a suspicion for ≥T1a disease and the lesion was >15 mm (January 2017 to April 2023). This was compared with a conventional EMR predominant approach (CEA), where ESD was only performed in cases suspicious for deep submucosal invasion or T1b disease (February 2013 to December 2016). The primary outcome was curative oncologic resection (R0 resection with favorable histologic features).

Results

A total of 298 resections were performed in 298 patients (68 UEA, 230 SRAB). Median lesion size was 20 mm (IQR 15-30). T1a adenocarcinoma was identified in 83 (27.9%) and T1b in 58 (19.5%), of which 31 (10.4%) were SM1. Comparing T1a and T1b disease, the rate of enbloc resection (CEA 12 [46.2%] vs SRAB 103 [90.4%]; P<0.001), R0 excision (CEA 7 [26.9%] vs SRAB 86 [74.8%]; P<0.001) and curative resection (CEA 6 [23.1%] vs SRAB 58 [50.4%]; P=0.011) was higher in the SRAB group. Among all T1a and T1b-SM1 cases with favorable histology, which underwent ESD, 39/46 (84.8%) were R0 excisions and are likely cured. There were no significant differences in adverse events (P>0.788 for all).

Conclusion

A selective resection algorithm optimizes oncologic outcomes for Barrett’s adenocarcinoma and mitigates the risk of piecemeal resection of cancers.

Disclosure

Michael J. Bourke: Research Support: Olympus, Cook Medical, Boston Scientific.

Clinical Case Summary

A 13-year-old boy presented with abdominal distention, recurrent hypoglycemia, and self-resolving jaundice. Clinical examination revealed growth retardation and hepatosplenomegaly. Blood work revealed anemia, thrombocytopenia, elevated aspartate and alanine transaminase levels, and raised plasma cholesterol and triglycerides. Ultrasound showed an enlarged liver with surface irregularity, splenomegaly, and a dilated portal vein. Etiological work-up for cirrhosis was positive for hepatitis B (HBV) surface antigen (HbsAg) and antibodies for HBV core and envelope antigens (anti Hbc, antiHbe) but an undetectable HBV DNA level. HBV was considered to be an unlikely cause of cirrhosis due to the young age of the patient, hence further metabolic and genetic work-up was done. Tests for Wilson’s and autoimmune liver disease were negative. Liver biopsy revealed a distorted lobular architecture with nodules, thin septae, and portal fibrosis. Hepatocytes showed marked swelling and pyknotic nuclei, and negative HbsAg immunostaining. Molecular analysis revealed a novel mutation in the exon 3 of the PHKG2 gene (c.98G>T, p.Gly33Val). The patient was diagnosed with cirrhosis due to GSD IXc with inactive chronic hepatitis B. His symptoms resolved with an optimized diet of corn starch, high-protein and vitamin supplementation. The importance of liver transplantation was also discussed with the family.

Introduction

Informed consent (IC) serves as the ethical foundation for all medical interventions, empowering patients to make informed, autonomous decisions while safeguarding clinicians. Barriers such as limited health literacy and document complexity may hinder comprehension^1,2. This study evaluated the comprehensibility, readability, and effectiveness of the documents provided for IC and instructions for endoscopic procedures.

Aims & Methods

Outpatients undergoing endoscopic procedures completed a questionnaire assessing their understanding of IC, preparation instructions, and adherence to guidelines. Patient confidence and document comprehensibility were assessed through self-reported scales. Readability was assessed using Flesch Reading Ease score adapted for portuguese (FRE-PT)³.

Results

Among 186 participants (mean age: 58.1 ± 16.1 years), 76.9% reported full-extent reading of the provided instructions and IC document. Patients with primary education (≤4th grade) were less likely to read the documents fully (59.2% vs. 83.2%, p < 0.001) and were independently associated with the need for additional assistance (OR 5.65, 95% CI: 1.92 - 16.68, p = 0.002). Full-extent reading was independently associated with greater risk awareness (OR 5.52, 95% CI: 2.37 - 11.55, p < 0.001), reduced need for additional assistance (OR 0.22, 95% CI: 0.09 - 0.51, p < 0.001), and higher compliance with medication guidelines (75.7% vs. 45.8%, OR 3.42, 95% CI: 1.28 - 9.20, p = 0.015). Patients with primary education rated document’s comprehensibility lower (median:8, IQR 7-10) compared to those with higher education (median: 10, IQR 8 - 10, p < 0.001) and reported lower levels of confidence and preparation for the procedure (median: 8, IQR 7 - 10 vs. median: 9, IQR 8 - 10; p = 0.018). Outcomes did not differ significantly between patients aged 65 years or older compared to younger patients. FRE-PT scores classified readability as ‘’very difficult’’ for both upper endoscopy (20.87) and colonoscopy (26.00).

Conclusion

Full-extent reading IC and instruction documents reduces the need for assistance, improves compliance with pre-procedural measures, risk awareness and patient confidence. However, the document’s complexity and difficult readability disproportionately challenge and discourage patients with limited education. Future research should explore strategies to foster more equitable informed decision-making.

References

1. Protheroe J, Rowlands G. Matching clinical information with levels of patient health literacy. Nurs Manag (Harrow). 2013;20(3):20-21. doi:10.7748/nm2013.06.20.3.20.e1095
2. Ley R, Forio T. The use of readability formulas in health care. Psychol Health Med. 1996;1(1):7-28.
3. Martins TBF, Ghiraldelo CM, Nunes MGV, Oliveira Junior ON. Readability formulas applied to textbooks in Brazilian Portuguese. 1996.