Introduction

Proton pump inhibitors (PPIs) have become clinically essential agents as a treatment strategy for gastroesophageal reflux diseases (GERD). PPI use has increased over time including continuous and longer-time users, which leads growing concern about PPIs side-effect. Endoscopic gastric mucosal changes possibly associated with PPIs use, such as fundic gland polyps (FGPs), hyperplastic polyps, multiple white and flat elevated lesions (MWFL), cracked or cobblestone-like mucosa (CCLM) and black spots, have been reported in recent years. Histopathologically, these endoscopic features are suggested to be associated with parietal cell enlargement, cystic dilation of fundic glands and foveolar epithelial hyperplasia. It is also well known that Gastrin level is hormonally elevated resulted from acid inhibition in PPIs users. Considering that gastrin has a trophic effect on the gastric epithelial cells including enterochromaffin-like (ECL) cell and parietal cell, PPI-related gastric mucosal changes might be related with hypergastrinemia. Yet, little is known about the relationship between these gastric epithelial changes and gastrin level among PPI users.

Aims & Methods

We hypothesized that hypergastrinemia in long-time PPI users might be associated with endoscopic gastric mucosal changes. The patients who have been taken PPI over 1 year between January 2021 and March 2022 in Hattori clinic and Hirano clinic were enrolled. Fasting blood samples were collected from participants just before oesophagogastroduodenoscopy (EGD) and serum gastrin level was measured. 3 endoscopists retrospectively evaluated the presence of PPI-related gastric mucosal changes. The participants were classified into 3 groups by tertiles of gastrin level: <255 pg/mL(Low), ≥255 pg/mL, <495 pg/mL(Middle), ≥495 pg/mL(High) and evaluated for the PPI-related gastric mucosal change.

Results

A total of 57 patients were enrolled in the present study. Median (IQR) age was 73.0 (68.0-77.0) years, 22(38.6%) were male, 6 (10.5%) was current smokers, and 18 (31.6%) were alcohol users. Of 57 patients, 26 (45.6%) had been taking PPI over 10 years. Median (IQR) gastrin, pepsinogenI and pepsinogenII level were 310(190-510)pg/mL, 117.0 (79.1-166..0)ng/mL and 17.9 (11.4-22.4)ng/mL. The overall prevalences of FGPs, CCLM, hyperplasticity polyps, MWFL and black spots were 34 (59.6%), 23 (40.4%), 23 (40.4%), 10 (17.5%) and 4 (7.0%), respectively.
Among 3 groups, there were significant differences for the prevalences of CCLM and FGPs. Regarding CCLM, higher gastrin group had higher prevalence than the low gastrin group, i.e. the middle gastrin group vs the low gastrin group (OR, 5.28; 95% CI,1.28-21.78; P = .021) and the high gastrin group vs the low gastrin group (OR,7.13; 95% CI,1.58-32.14; P = .011) (p-trend=.0218). On the contrary, lower prevalence of FGPs was observed in the high gastrin group, i.e. the high gastrin group vs the low gastrin group (OR,0.24; 95% CI,0.06-0.96; P = .043)(not significant difference for trend). There were not significant differences for the prevalences of hyperplastic polyps, MWFL and black spots.

Conclusion

In the current study, it was suggested that higher gastrin level might promote cracked or cobblestone-like mucosal change and inhibit fundic gland polyp formation. Hypergastrinemia resulting from PPI use might affect the gastric mucosal changes.

Introduction

In patients with upper gastrointestinal bleeding (UGIB), the European Society of Gastrointestinal Endoscopy (ESGE) recommends adopting the following definitions regarding the timing of upper GI endoscopy: urgent (6-12h), early (≤24h), and delayed (>24h) (1). There is no consensus definition of emergent endoscopy, but previous publications use the timeline of <6h (2).
Early endoscopy is associated with better outcomes, and guidelines suggest that it should be performed within this time frame (1).
Last ESGE guideline about variceal bleeding (VB) suggests performing urgent endoscopy in this context (3). This is based on a meta-analysis showing lower overall mortality when endoscopy was performed <12h compared to >12h (4). Surprisingly, ESGE concludes that the optimal timing in this setting is controversial due to a lack of high-level evidence. In fact, except for this study, all the others examining this aspect show that performing endoscopy before 12h does not provide benefits (5,6).

Aims & Methods

We aim to compare whether urgent endoscopy (6-12h) provides benefits to VB and explore predictors for mortality.
Methods: Retrospective analysis of a prospective registry of UGIB patients admitted to 'Virgen de las Nieves University Hospital' (2013-2020). VB was defined as that coming from gastric or esophageal varices. Endoscopy timings were defined according to ESGE: emergent (<6h), urgent (6-12h), early (≤24h) and delayed (>24h) (1).
Main outcomes were in-hospital (endoscopy therapy, transfusion, rebleeding, misbalance of chronic condition, hospital stay, and mortality) and delayed-6 months (bleeding, cardiovascular events, mortality). Statistical analysis was performed using SPSS.

Results

1459 UGIB patients were collected, 216 with VB.
Statistical differences in main outcomes are shown in Table 1 (each letter in the subscript denotes column proportions that do not differ significantly from each other). No differences were found for the other outcomes.

Timing (% patients)	<6h (39.7%)	6-12h (28.8%)	12-24h (17.4%)	24h (2.7%)	p
Endoscopy therapy	85.1% a	63.5% b	65.8% b	66.7% b	0.014
Misbalance of chronic condition	48.3% a	30.2% b	23.7% b	50% a	0.026
Rebleeding	22.1% a	7.9% b	7.9% b	16.7% a	0.037
In-hospital mortality	27.4% a	13.6% b	11.1% b	50% a	0.025

We also compared basal characteristics and found differences in MAP(ASH) score≥2 (92.3% vs. 66.7% vs. 77.4% vs. 75%; p=0.003) and GBS≥12 (69% vs. 44.4% vs. 52.6% vs. 83.3%; p= 0.011).
Independent risk factors for in-hospital mortality were MAP(ASH)≥2 (1.26, 95% CI 1.03-1.54), misbalance of chronic condition (OR 9.92, 95% CI 3.56-27.61, p=0.000), and rebleeding (OR 3.95, 95% CI 1.45-10.79, p=0.007). The timing of endoscopy performing was not an independent prognostic factor for mortality.
We also conducted subgroup analysis to assess whether performing endoscopy before 12h provides benefits in other UGIB patients, without finding differences for patients with non-variceal bleeding or in those at higher risk of poor outcomes (GBS≥12, MAP(ASH)≥2, ASA≥3).

Conclusion

Our study highlights, in line with the majority of available ones (5,6), that endoscopy before 12h does not provide a benefit in patients with VB. This necessitates a reconsideration of the ESGE recommendation. Patients with endoscopy performed before 6 or after 24h have poor outcomes. However, multivariate analysis shows that the timing of endoscopy is not an independent prognostic factor for mortality. On the other hand, the decompensation of basal chronic disease and the severity of bleeding (determined by MAP(ASH) and rebleeding) are the determinants of patient outcomes.

References

1. Gralnek IM, Stanley AJ, Morris AJ, Camus M, Lau J, Lanas A, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy. 2021 Mar;53(3):300-332.
2. Laursen SB, Leontiadis GI, Stanley AJ, Møller MH, Hansen JM, Schaffalitzky de Muckadell OB. Relationship between timing of endoscopy and mortality in patients with peptic ulcer bleeding: a nationwide cohort study. Gastrointest Endosc. 2017 May;85(5):936-944.e3.
3. Gralnek IM, Camus Duboc M, Garcia-Pagan JC, Fuccio L, Karstensen JG, Hucl T, et al.. Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Nov;54(11):1094-1120.
4. Bai Z, Wang R, Cheng G, Ma D, Ibrahim M, Chawla S, Qi X. Outcomes of early versus delayed endoscopy in cirrhotic patients with acute variceal bleeding: a systematic review with meta-analysis. Eur J Gastroenterol Hepatol. 2021 Dec 1;33(1S Suppl 1):e868-e876.
5. Zhang W, Huang Y, Xiang H, Zhang L, Yuan L, Wang X, et al. Timing of endoscopy for acute variceal bleeding in patients with cirrhosis (CHESS1905): A nationwide cohort study. Hepatol Commun. 2023 May 4;7(5):e0152.

Introduction

Non-variceal upper gastrointestinal bleeding (NVUGI) represents a significant gastrointestinal disorder with elevated mortality rates (1). Non-steroidal anti-inflammatory drugs (NSAIDs) have been firmly established as a risk factor for NVUGI, yet their precise impact on clinical outcomes remains insufficiently defined (2,3). Conversely, proton pump inhibitors (PPIs) have shown efficacy in reducing the incidence of NVUGI associated with NSAIDs. However, the extent of their influence on the clinical outcomes of NVUGI remains inadequately substantiated. Therefore, it is necessary to study the impact of these drugs on the clinical outcomes of patients with NVUGI.

Aims & Methods

The primary objective of our study is to compare the outcomes of NVUGI patients using NSAIDs with or without PPIs against those who did not use either medication. We conducted a retrospective analysis at a Spanish tertiary hospital, encompassing NVUGI cases from 2013 to 2022. NVUGI was defined as hematemesis or melena accompanied by a two-point decrease in hemoglobin or hemodynamic instability. Key clinical outcomes included the necessity for intervention (endoscopic, radiological, or surgical) and in-hospital mortality. Additionally, we compared baseline characteristics and pertinent clinical results such as rebleeding and delayed cardiovascular events. Statistical analysis was performed using SPSS.

Results

​A total of 1200 cases were included, with 6.6% undergoing concomitant treatment with PPIs and NSAIDs, and 15.7% utilizing NSAIDs alone. Patients who took NSAIDs alone were younger (57 years vs. 66 in both other groups) and had a lower rate of comorbidities. Table 1 presents risk scores and outcome comparisons among the three groups. Statistical differences were observed, revealing lower acute mortality (9.6% vs. 7 vs. 2.8%, p=0.011) and reduced need for intervention (74% vs. 69.6 vs. 57.8%, p<0.001) in the group using NSAIDs alone. In multivariate analysis, MAP(ASH) > 2 (OR: 8, CI: 3-21, p<0.001) and ASA > 2 (OR: 4.4, CI: 1.7-11.4, p:0.002) emerged as independent risk factors for acute mortality, with an elevated MAP(ASH) score (OR: 8.8, CI: 5.9-13, p<0.001) being the sole independent factor explaining the need for intervention.

	Naive	NSAIDs and PPIs	NSAIDs without PPIs	P
ASA 3-4	596 (64,3%)	50 (63,3%)	63 (33,7%)	<0,001
MAPASH>2	448 (59,3%)	39 (65%)	52 (34,4)	<0,001
Need for intervention	691 (74%)	55 (69,6%)	108 (57,8%)	<0,001
Rebleeding	96 (10,3%)	9 (11,4%)	6 (3,2%)	0,008
Acute mortality	86 (9,6%)	5 (7%)	5 (2,8%)	0,011
Mortality at 6 months	77 (8,8%)	7 (9,3%)	7 (3,8%)	0,075
Delayed Cardiovascular event	77 (8,7%)	3 (3,9%)	4 (2,2%)	0,004
Delayed rebleeding	145 (16,4%)	15 (19,5%)	6 (3,3%)	<0,001

Conclusion

Patients abstaining from NSAIDs or those concurrently undergoing PPI therapy exhibited a higher incidence of intervention or acute mortality compared to those solely using NSAIDs. Through multivariate analysis, our study indicates that bleeding severity and baseline comorbidities, expressed by elevated MAP(ASH) scores and ASA classification, are pivotal factors influencing the clinical outcomes of NVUGI. In summary, the use of NSAIDs or PPIs to safeguard against gastrointestinal lesions induced by these drugs did not demonstrate a discernible impact on the short-term outcomes of patients with non-variceal upper gastrointestinal bleeding.

References

1. Lakatos L, Gonczi L, Lontai L, Izbeki F, Patai A, Racz I, et al. Incidence, predictive factors, clinical characteristics and outcome of non-variceal upper gastrointestinal bleeding – a prospective population-based study from hungary. Journal of Gastrointestinal and Liver Diseases. 2021 Sep 1;30(3):327–33.
2. Durak MB, Şimşek C, Yüksel İ. Clinical Outcomes of Older Patients with Non-Variceal Upper Gastrointestinal Bleeding Taking Anti-Thrombotic or Non-Steroidal Anti-Inflammatory Agents. Turkish Journal of Gastroenterology. 2023 Sep 1;34(9):918–24.
3. Åhsberg K, Höglund P, Kim WH, Von Holstein CS. Impact of aspirin, NSAIDs, warfarin, corticosteroids and SSRIs on the site and outcome of non-variceal upper and lower gastrointestinal bleeding. Scand J Gastroenterol. 2010 Dec;45(12):1404–15.

Introduction

Copeptin is a stable surrogate biomarker for the activation of the arginine vasopressin (AVP) system [1] as occurs in patients with cirrhosis and clinically significant portal hypertension (CSPH). Specifically, CSPH-induced haemodynamic alterations characterized by reduced peripheral vascular resistance and splanchnic hyperemia cause subsequent AVP system activation [2]. We aimed to evaluate serum copeptin levels (i) in different stages of cirrhosis and (ii) their prognostic value for clinical events in a cohort of stable outpatients with cirrhosis.

Aims & Methods

Stable outpatients with cirrhosis undergoing hepatic venous pressure gradient (HVPG) measurements and available copeptin levels were included; while patients with liver transplantation, malignacy, vascular liver disease, transjugular intrahepatic portosystemic shunt, heart failure and infection were excluded. Patients were stratified into 6 subgroups (S0-S5) for their clinical stage of cirrhosis, with S0-S2 representing compensated cirrhosis (S0: subclinical portal hypertension (PH) with an HVPG of 6-9 mmHg, S1: CSPH without varices, S2: CSPH with varices) and S3-S5 decompensated cirrhosis (S3: history of variceal bleeding, S4: non-bleeding decompensation, S5: further decompensation). Competing risk regression models were used to evaluate the association between copeptin levels and the risk of acute on chronic liver failure (ACLF) and liver-related death (LRD). Liver transplantation was considered as a competing event. Our previously established serum copeptin cut-off at >11.4 pmol/L [3] was used to stratify the patients into a high vs. low AVP system activation group.

Results

In total, 475 patients (S0: n=49, S1: n=53, S2: n=75, S3: n=22, S4: n=156, S5: n=120) with male predominance (72.6%; median age: 57.1 years) were included. Median follow-up time was 26.4 months. Median copeptin levels significantly increased throughout the substages of ACLD (from S0: 7.5 pmol/L to S5: 14.3 pmol/L; p<0.001). Patients with ascites had significantly higher copeptin levels (11.3 pmol/L vs. 7.2 pmol/L in non-ascites patients; p=<0.001).
Serum copeptin correlated significantly with C-reactive protein (ρ=0.281; p<0.001) and interleukin-6 levels (ρ=0.416; p<0.001) in patients with decompensated cirrhosis.
AVP system activation (i.e., Copeptin high >11.4 pmol/L) was found in n=194/475 (40.8%) patients. Patients with high-Copeptin had a significantly higher median MELD-Na (15 vs. low-Copeptin: 12; p<0.001) as well as significantly lower median mean arterial pressure (97 mmHg vs. low-Copeptin: 101 mmHg; p=0.027). The cumulative incidence of ACLF and LRD was significantly higher in patients with high-Copeptin at 1 year (ACLF: 24.1% vs. 4.0%; LRD: 21.9% vs. 4.0%), 2 years (ACLF: 32.0% vs. 7.2%; LRD: 26.7% vs. 6.3%) and 3 years (ACLF: 34.4% vs. 11.6%; LRD: 29.9% vs. 11.2%) of follow-up (p<0.001 for ACLF and LRD).
In competing risk regression adjusted for age, Child Turcotte Pugh score, creatinine, sodium and HVPG, higher levels of copeptin were independently predictive of ACLF (adjusted subdistribution hazard ratio [asHR] per pmol/L: 1.01; 95% confidence interval [95%CI]: 1.00-1.01; p=0.014), as well as LRD (asHR: 1.01; 95%CI: 1.00-1.01; p=0.024).

Conclusion

In ACLD, copeptin levels are upregulated with increasing disease severity suggesting progressive AVP system activation, associated with hemodynamic dysregulation and systemic inflammation. High-Copeptin represents an independent risk factor for ACLF and LRD development.

References

1. Abudeif A, Hashim MS, Ahmed NM, Ahmed AO. Serum copeptin is associated with major complications of liver cirrhosis and spontaneous bacterial peritonitis. Clin Exp Hepatol. 2023;9(1):71-8.

2. Kerbert AJ, Weil D, Verspaget HW, Moréno JP, van Hoek B, Cervoni JP, et al. Copeptin is an independent prognostic factor for transplant-free survival in cirrhosis. Liver Int. 2016;36(4):530-7.

3. Hartl L, Jachs M, Desbalmes C, Schaufler D, Simbrunner B, Paternostro R, et al. The differential activation of cardiovascular hormones across distinct stages of portal hypertension predicts clinical outcomes. Hepatol Int. 2021;15(5):1160-73.