Introduction

Curent studies have proven that non-alcoholic fatty liver disease (NAFLD) impacts an important role in the development of risk factors for cardiovascular diseases. Comorbidities are a risk of a complicated course of coronary heart disease (CHD). The criteria for the effectiveness of treatment in medical practice are the duration and quality of life (QoL) of patients. The main tool for assessing quality of life in curent clinical research is questionnaires. The most common questionnaires widely used by scientists are the Medical Outcomes Study 36-Item Short-Form Health Status (SF-36) and EuroQoL-5D (EQ-5D).

Aims & Methods

The aim: To evaluate the indicators of QoL in patients with non-alcoholic steatohepatitis with coronary heart disease with stable angina pectoris in combination after complex therapy including ezetimibe and ursodeoxycholic acid.
Materials and methods: The prospective study included 145 patients with a verified diagnosis of CHD with stable angina pectoris II functional class combined with nonalcoholic steatohepatitis (NASH) and 100 patients with CHD without NASH. All 245 patients received basic CHD therapy: acetylsalicylic acid 100 mg once a day, ramipril 2.5 mg once a day, bisoprolol 2.5 mg once a day, and rosuvastatin - 20 mg once a day. To achieve the aim, 3 groups of patients were formed depending on the available metabolic factors (MFR): group 1-a (n=75) – patients had CHD+ NASH + MFR (arterial hypertension (AH), dyslipidemia, increased body weight or obesity) and group 1-b (n=70) – CHD+ NASH + AH, as well as group 2 (n=100) – CHD without NASH. Group 1-a patients received the basic therapy of CHD and ezetimibe 10 mg/1 time per day and UDCA 15 mg/kg/day 2 hours before bedtime, for 6 months, against the background of recommendations for lifestyle modification (LM). Group 1-b received basic therapy of CHD and UDHC 15 mg/kg/day 2 hours before bedtime, for 6 months, against the background of recommendations for LM (weight loss, hypocaloric diet). Group 2 patients received only the basic therapy of CHD.

Results

As the obtained results show, positive clinical dynamics from treatment were noted in patients of group 1-a who received complex therapy with the addition of ezetimibe and UDCA at p<0.05. Regarding the QoL indicators according to the SF-36 questionnaire after treatment, a tendency to improve most of its indicators was revealed, which is more clearly observed in patients of group 1-a. Analyzing the integrated indicators of physical and mental components of health on all scales of SF-36 revealed reliable positive dynamics on all scales of the questionnaire, which are best expressed in patients of group 1-а in comparison with group 1-b at p<0.05. The following indicators were most significantly affected: social functioning increased by 40.6 points in group 1-a, respectively, by 27.6 points in group 1-b at p<0.05; the value of the role of emotional problems increased by 55.7 points in group 1-a, respectively, by 40.3 points in group 1-b at p<0.05; general health increased by 56.9 points in group 1-a, respectively, by 45 points in group 1-b at p<0.05.

Conclusion

Complex therapy including ezetimibe and UDCA in patients with CHD combined with NASH is more effective compared to basic CHD therapy, as it reliably reduces the frequency of attacks of stable angina and the need for nitroglycerin. The effectiveness of the treatment of CHD combined with NASH is increased by the inclusion of ezetimibe and UDCA in the basic therapy and has a positive effect on the clinical course of CHD, QoL of patients and the patient's attitude to his own disease.

References

1. Chang WH, Mueller SH, Chung S-C, Foster GR, Lai AG. Increased burden of cardiovascular disease in people with liver disease: unequal geographical variations, risk factors and excess years of life lost. J Transl Med. 2022;20:1–13. https://doi.org/10.1186/s12967-021-03210-9
2. Hassen G, Singh A, Belete G, Jain N, la Hoz I, Camacho-Leon GP, et al. Nonalcoholic fatty liver disease: An emerging modern-day risk factor for cardiovascular disease. Cureus. 2022;14(5):1-15. https://doi.org/10.7759/cureus.2549
   
3. Janani K, Jain M, Vargese J, Srinivasan V, Harika K, Michael T, et al. Health-related quality of life in liver cirrhosis patients using SF-36 and CLDQ questionnaires. Clin Exp Hepatol. 2018;4(4):232–9. https://doi.org/10.5114/ceh.2018.80124
4. Lombardi R, Iuculano F, Pallini G, Fargion S, Fracanzani AL. Nutrients, genetic factors, and their interaction in non-alcoholic fatty liver disease and cardiovascular disease. Int J Mol Sci. 2020;21(22):87-91. https://doi.org/10.3390/ijms21228761
5. Simon TG, Corey KE, Cannon CP, Blazing M, Park J-G, O’Donoghue ML, et al. The nonalcoholic fatty liver disease fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe. Int J Cardiol. 2018;270:245–52. https://doi.org/10.1016/j.ijcard.2018.05.08
   
6. Zhou T, Guan H, Wang L et al. Health-related quality of life in patients with different diseases measured with the EQ-5D-5L: a systematic review. Front Public Heal. 2021;9:6755-63 https://doi.org/10.3389/fpubh.2021.675523
   

Disclosure

The authors declare that there is no conflict of interest and no financial interest in the preparation of this article.

Clinical Case Summary

Immune checkpoint inhibitor (ICI) related gastrointestinal (GI) toxicities are associated with increased incidence due to their rising use in cancer management.
We report a unique case of a late-onset immune-related enteritis in a 66-year-old man with metastatic melanoma, initially receiving dual ICI therapy (Ipilimumab – anti-CTLA4 and Nivolumab – anti-PD-1 agent). Аpproximately 18 months after being placed on Nivolumab maintenance monotherapy he presented with abdominal pain, peripheral edema and watery diarrhea up to 10 times a day. Infectious causes of diarrhea were excluded, including Cl.difficile, along with negative serology for CMV, EBV and HSV. Endoscopic evaluation revealed multiple deep ulcerations along the duodenum, proximal jejunum and terminal ileum with no involvement of the stomach and colon. Histological analysis was indicative of acute chronic small bowel inflammation with positive CMV-PCR and no signs of neoplasms or specific granulomas. Patient was placed on parenteral nutrition and peroral Valacyclovir with no significant improvement. Systemic steroid therapy was then initiated followed by a reduction in bowel movements, confirming the immune-mediated course of the disease.
After one-month follow up patient reported of persisting grade 1 diarrhea with elevated calprotectin levels while slowly tapering steroid dose. Control gastroscopy revealed remaining multiple ulcers at the descending duodenal part and jejunum. Second line therapy of Infliximab was then initiated, achieving complete response after three infusions. Corticosteroids were eventually slowly tapered off and Nivolumab was permanently ceased.
Ruling out all other possible causes, the diagnosis of late-onset immune-mediated enteritis was made. Although anti-PD-1 related GI toxicities seem to be less frequent with typical onset within three months after initiation, long-term surveillance and therefore prompt recognition is encouraged to avoid life-threatening complications.

References

1. CT showing diffuse enteritis
2. Endoscopic findings in the descending duodenal part and terminal ileum
3. Histopathological image
4. Follow up gastroscopy findings

Clinical Case Summary

An 86-year-old woman with newly diagnosed metastatic, poorly differentiated gastric adenocarcinoma commenced palliative treatment with FOLFOX chemotherapy (initially at 50% dose due to pending DPYD results, later escalated to full dose) and nivolumab immunotherapy. Initial cycles were tolerated, with granulocyte-colony stimulating factor (G-CSF) support initiated after the second cycle due to observed neutropenia. However, following both the third and fourth cycles of chemoimmunotherapy, the patient developed acute systemic illness within 24 hours. This was characterised by acute confusion, fever, lymphadenopathy, and systemic inflammatory features. Blood investigations revealed pronounced leukocytosis with neutrophilia (WCC >30 x10⁹/L), elevated C-reactive protein (>200 mg/L), and acute kidney injury necessitating hospital admission on both occasions. Comprehensive septic screens, including blood, urine cultures, and viral PCR panels, were negative. G-CSF administration was considered as a differential, though this did not entirely fit with temporality of events given the second reaction post-cycle four occurred without the patient having taken G-CSF, raising suspicion for an immunotherapy-mediated reaction. Given the consistent temporal association with nivolumab administration and the complete resolution of these severe systemic symptoms following its discontinuation from the fifth cycle onwards, checkpoint inhibitor-related cytokine release syndrome (CRS) was considered the most likely diagnosis. Chemotherapy was continued at a reduced dose (75% FOLFOX) and was well tolerated without recurrence of the systemic inflammatory episodes. This case underscores the rare but significant potential for CRS in elderly patients with solid tumours receiving PD-1 inhibitors in combination with chemotherapy, highlighting the importance of considering this diagnosis when faced with acute, unexplained systemic inflammatory responses following immunotherapy administration.

References

Figure 1: Timeline depicting chemotherapy and nivolumab administration, G-CSF use, and the onset and resolution of systemic symptoms after cycles 3 and 4.
Figure 2: Graphical representation of serial white blood cell counts and C-reactive protein levels, demonstrating the marked elevation during the suspected CRS episodes.

Clinical Case Summary

A 76-year-old male liver transplant recipient (originally HBV-associated cirrhosis with prior HCC, transplanted in 1998) presented for routine follow-up in January 2025 without complaints. A few days later, a superficial leg vein thrombosis was diagnosed by his general practitioner, and he was started on rivaroxaban. 21 days later, he presented to the emergency room with increasing weakness and melaena. At presentation, he was severely anaemic (haemoglobin 6.5 g/dL, previously 14.5 g/dL) with a lactate of 1.5 mmol/dL and an INR of 1.4, but stable kidney and liver function. Emergency gastroscopy showed active bleeding near the major duodenal papilla with clotted blood covering it. A side-view endoscopy was performed, but due to the bleeding proper visualization of the site and thus bleeding control was not possible. Consequently, CT angiography was performed and described active bleeding from the gastroduodenal artery correlating to the endoscopically visualized bleeding site.

References

Illustrative Material:
Endoscopic image (forward-view): Fresh blood and clot in the papillary region, swollen mucosa

Introduction

In Primary Sclerosing Cholangitis (PSC), progressive fibro-inflammatory destruction of the biliary epithelium leads to biliary strictures. Magnetic resonance imaging and endoscopic retrograde cholangioscopy (ERC) are the standard imaging methods for PSC but both describe strictures indirectly as filling defects and absence of bile fluid or contrast medium. Therefore, direct visualization of the biliary mucosal phenotype by single-operator cholangioscopy (SOC) might be more accurate in stratifying the heterogeneous disease activity of PSC.

Aims & Methods

The aim of this study was to compare results of ERCs with and without additional single-operator cholangioscopy (SOC) in PSC patients and to characterize biliary mucosal phenotypes. We intended to correlate the mucosal phenotype with disease activity, hepatobiliary malignancy and transplant-free survival. 111 ERCs of PSC patients, including 56 ERCs with additional SOC that were performed from 2012 until 2021 at the University Hospital Bonn were analyzed retrospectively. We applied the Edmonton classification described by Sandha et al. (1) to distinguish between four phenotypes: 1a) acute inflammatory, 1b) chronic inflammatory, 2) fibrostenotic, 3) nodular/mass forming.

Results

We found that 50% of the PSC cases did not show uniform mucosal changes, but heterogeneous aspects with at least two phenotypes next to each other. The fibrostenotic type was most commonly observed (69.9%), followed by the chronic inflammatory type (39.3%). Fluoroscopically guides forceps biopsies showed mainly inflammation with fibrosis (37.8%) and fibrotic bile duct changes without inflammation (26.7%). However, biopsies targeted under cholangioscopic view revealed bile duct inflammation in 60% and purely fibrotic changes in only 8.6%. The frequency of biliary dysplasia or malignancy did not differ between patients receiving SOC or ERC only. Patients with a chronic inflammatory phenotype had significantly less severe bile duct strictures (p=0.05), lower bilirubin (p=0.007) and aminotransferases (p< 0.02). Similarly, the fibrostenotic type was characterized by less complex extrahepatic strictures (p=0.03). In contrast, the acute inflammatory phenotype was associated with significantly more advanced bile duct strictures (p=0.007), higher bilirubin (p=0.01) and more frequent pruritus (p=0.028). The transplant-free survival of the acute inflammatory phenotype was significantly shorter (13.5 months) compared to those without these mucosal changes (21.2 months) (p=0.02). In univariate Cox regression analysis, hepatobiliary malignancy, age at first diagnosis, bilirubin, degree of biliary strictures as well as the acute inflammatory phenotype (p=0.03) were associated with transplant-free survival. The acute inflammatory type remained as an independent risk factor for shorter transplant-free survival in multivariable regression analysis (p=0.002). Additional SOC during ERC was not associated with higher complication rates (fever p=0.21, abdominal pain p=0.53, pancreatitis p=0.65, perforation p=0.56, days of hospitalization p=0.11).

Conclusion

Biopsies sampled under cholangioscopic view revealed inflammation in fluoroscopic inconspicuous bile ducts. The cholangioscopic stratification of the biliary mucosal phenotype, which eludes fluoroscopic assessment, is clinically and prognostically relevant and should be taken into consideration when identifying at-risk patients and in the endoscopic management of strictures.

References

(1) Sandha G, D'Souza P, Halloran B, Montano-Loza AJ. A Cholangioscopy-Based Novel Classification System for the Phenotypic Stratification of Dominant Bile Duct Strictures in Primary Sclerosing Cholangitis-the Edmonton Classification. J Can Assoc Gastroenterol. 2018 Dec;1(4):174-180. doi: 10.1093/jcag/gwy020. Epub 2018 May 11. PMID: 31294358; PMCID: PMC6542244.

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly nonalcoholic fatty liver disease, NAFLD) has become the leading cause of chronic liver disease worldwide. It has been suggested that early-life factors play a major role in its development and progression with small vulnerable newborns (i.e., preterm birth, low birthweight or small for gestational age (SGA]) being at higher risk.

Aims & Methods

To investigate the associations of preterm birth, low birthweight, and small for gestational age (SGA) with later life MASLD through a systematic review and meta-analysis of existing literature.
We searched Medline, EMBASE, and Web of Science up to 11 March 2025 for studies on birthweight, gestational age, and birthweight for gestational age and risk of MASLD. Search results were screened by two independent reviewers. A study protocol was pre-registered in the PROSPERO database (CRD420251005153) and results were reported according to the PRISMA guidelines. Meta-analysis (random-effects model) was performed on low birthweight, preterm birth, and SGA.

Results

A total of 3,794 publications were identified in the search. After screening of 1,431 titles and abstracts, 46 studies were eligible for full-text evaluation. In total, 37 studies were included in the systematic review, and among these, 11 were included in the meta-analysis (n= 12,580 individuals).
Data on preterm birth were available in three studies (2,972 individuals). Preterm birth was associated with an increased odds of MASLD (odds ratio, OR: 2.47 [95% CI, 1.76-3.45]). Data on low birthweight were available in four studies (3,788 individuals). Low birthweight was not associated with MASLD (OR: 1.47 [95% CI, 0.83-2.60]). Data on SGA were available in seven studies (10,336 individuals). SGA was associated with an increased odds of MASLD (OR: 2.46 [95% CI, 1.44-4.20]).

Conclusion

Small vulnerable newborns, i.e. those born preterm, or SGA are at ~2.5-fold increased risk of developing MASLD later in life. These findings highlight the need for increased prevention efforts to reduce the number of adverse birth outcomes and structured lifestyle recommendations for these high-risk newborns.

Disclosure

FE has served as an advisory board member for Boehringer Ingelheim.
JFL has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen Corporation. JFL has also received financial support from MSD/Merck developing a paper reviewing national healthcare registers in China, and for a collaboration on inflammatory bowel disease. JFL also has a research collaboration on celiac disease with Takeda.
The other authors report no disclosures relevant to the manuscript.

Introduction

Functional dyspepsia (FD) is one of the most frequent disorders of gut-brain interaction, but according to the recent UEG consensus there is a lack of effective treatment options.(1) An important role for duodenal immune activation and increased mucosal permeability has been implied in the pathophysiology of FD. In a recent in vitro study on duodenal biopsies from FD patients palmitoylethanolamide (PEA), an endogenously produced anti-inflammatory compound, was shown to stabilize acid-induced activation of mast cells.(2) PEA is produced in several cell types and tissues to counteract inflammatory and other noxious responses, and diminished levels have been reported in duodenal biopsies from FD patients.(2)

Aims & Methods

In this randomized double blind placebo-controlled trial, we aimed to evaluate the effect of PEA supplementation on symptoms, mucosal integrity and duodenal low grade inflammation. After a 2-week run-in, patients were randomized to placebo or PEA 400 mg t.i.d. for 8 weeks. Before and after the treatment phase, patients underwent upper gastrointestinal endoscopy with biopsies and a ¹³C-octanoic acid gastric emptying breath test to measure gastric emptying half time (GE T_1/2). Biopsies were used to measure transepithelial electrical resistance (TEER) and paracellular flux of 4kDa-fluorescein labelled dextran (FITC D4) in Ussing chambers and to count mast cells. Symptoms were recorded using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) and Leuven Postprandial Distress Scale (LPDS). The primary endpoint was the improvement in LPDS score. Symptoms and pathophysiological parameters were compared between PEA and placebo after 8 weeks of treatment.

Results

In this study, 61 patients were included of which 33 were assigned to placebo and 28 to PEA. The baseline characteristics are shown in Table 1. After treatment, no significant differences were found between the PEA and placebo group regarding LPDS scores (1.5±0.2 vs. 1.3±(0.2), p=0.47), GE T_1/2 (83 (76-98) vs. 95 (72-109) min, p=0.57), TEER (27.3±0.8 vs. 28.0±1.0 Ω * cm², p=0.21), and duodenal mast cell counts (589±43 vs. 557±34 mast cells / mm², p=0.56). FITC D4 flux tended to be lower after PEA (27.9±1.9 vs. 33.3±2.2 pmol, p=0.06), with a more robust effect in patients taking a proton pump inhibitor (Δ FITC D4 flux -3.8±3.4 vs. 7.2±2.8 pmol, p=0.027). In patients that received PEA, the Δ FITC D4 flux correlated negatively with the Δ total PAGI-SYM score (r -0.49, p=0.02) and Δ of mast cell counts correlated positively with Δ PAGI-SYM fullness subscale (r=0.49, p=0.04).

Conclusion

In FD, PEA does not improve gastrointestinal symptoms but improves duodenal barrier function mainly in patients that are taking a PPI. The interaction between PEA and PPI and its relevance for disorders of gut-brain interaction deserves further study.

References

1: Wauters L, Dickman R, Drug V, Mulak A, Serra J, Enck P, Tack J; ESNM FD Consensus Group; Accarino A, Barbara G, Bor S, Coffin B, Corsetti M, De Schepper H, Dumitrascu D, Farmer A, Gourcerol G, Hauser G, Hausken T, Karamanolis G, Keszthelyi D, Malagelada C, Milosavljevic T, Muris J, O'Morain C, Papathanasopoulos A, Pohl D, Rumyantseva D, Sarnelli G, Savarino E, Schol J, Sheptulin A, Smet A, Stengel A, Storonova O, Storr M, Törnblom H, Vanuytsel T, Velosa M, Waluga M, Zarate N, Zerbib F. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia. United European Gastroenterol J. 2021 Apr;9(3):307-331. doi: 10.1002/ueg2.12061. PMID: 33939891; PMCID: PMC8259261.
2: Sarnelli G, Pesce M, Seguella L, Lu J, Efficie E, Tack J, Elisa De Palma FD, D'Alessandro A, Esposito G. Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia. Cell Mol Gastroenterol Hepatol. 2021;11(3):841-855. doi: 10.1016/j.jcmgh.2020.10.001. Epub 2020 Oct 14. PMID: 33065341; PMCID: PMC7858681.