Introduction

Antithrombotic drugs (AT) pose an increased risk of upper gastrointestinal bleeding (UGIB), and their discontinuation carries the risk of thromboembolic events, presenting a challenge for clinicians (1,2). Clinical practice guidelines advocate for a restrictive approach, recommending non-discontinuation and/or early reintroduction based on the drug and its indication (3).
Despite available literature, controversy persists regarding the outcomes of patients with UGIB on antithrombotic therapy, both in the short and long term, as well as the potential impact of drug discontinuation (4,5).

Aims & Methods

Aim:
To determine the impact of ATs on in-hospital and delayed outcomes. Also, to determine whether suspension and resumption influenced delayed outcomes.
Methods:
Prospective registry analysis of UGIB patients between 2013-2021. Anticoagulants and antiplatelets were classified as AT drugs. Outcomes examined included in-hospital mortality and delayed-6 months cardiovascular, bleeding and mortality events.

Results

1345 patients were included, with 21.7% on anticoagulants and 19.1% on antiplatelets.
Patients on ATs were older (73 vs. 59 years; p<0.0001) and had a higher rate of comorbidities, has longer delay of endoscopic performance (11±11h vs. 9.6±8h; p=0.027), with gastric erosions being more usual (14.2% vs.9.1%; p=0.006). Table shows main outcomes.

	Non-AT (n=839)	AT (n=506)	P	Aspirin (n=195)	Thienopyridine (n=29)	Double antiaggregating (n=24)	VKA (n=179)	NACO (n=49)
Endoscopy therapy	48.3%	38.5%	0.001	75 (38.5%)	12 (41.4%)	7 (29.2%)	62 (34.6%)	20 (40.8%)
Rescue therapy	6.1%	3.8%	0.083	8 (4.1%)	17 (58.6%)	0	4 (2.2%)	1 (2%)
Rebleeding	10.5%	9.7%	0.702	20 (10.3%)	1 (3.4%)	18 (75%)	12 (6.7%)	4 (8.2%)
Transfusion	56.3%	66.2%	0.000	127 (65.1%)	17 (58.6%)	0	115 (64.2%)	41 (83.7%)
In-hospital mortality	12%	8%	0.028	14 (7.2%)	0	1 (4.2%)	13 (7.3%)	1 (2%)
Delayed cardiovascular event	3.4%	13.7%	0.000	18 (9.2%)	5 (17.2%)	1 (4.2%)	31 (17.3%)	12 (24.5%)
Delayed hemorrhagic event	12.9%	22.9%	0.000	43 (22.1%)	5 (17.2%)	6 (25%)	41 (22.9%)	12 (24.5%)
Delayed mortality	6%	9.4%	0.034	17 (8.7%)	2 (6.9%)	2 (8.3%)	19 (10.6%)	4 (8.2%)

AT suspension <72h was associated with increased in-hospital mortality (14.9% vs. 2.3%; p=0.001), especially <24h (20.9% vs. 2.6%; p<0.0001).
Delayed mortality was higher in patients on ATs who suspended them more than 7 days (17% vs.8.7%; p= 0.033), with no differences when last <72h. Suspension/reintroduction have no effect on other delayed outcomes.
Multivariate analysis identified ASA≥3 (HR 12.20;95%CI 3.69-56-92; p<0.001), disseminated malignancy (HR 4.73; 95%CI 1.92-11.42; p=0.001) and rebleeding (HR 19.25; 95%CI 9.07-43.04) as independent risk factors for in-hospital mortality, with AT therapy (HR 0.27; 95%CI 0.13-0.55; p<0.001), NSAIDS (HR 0.26; 95%CI 0.07-0.75; p=0.023), endoscopic therapy (HR 0.49; 95%CI 0.24-0.96; p=0.040) and hemoglobin levels being protectives factors HR 0.80; 95%CI 0.69.0.93; p=0.004).
Logistic regression analysis for delayed mortality showed that age (HR 1.04; 95%CI 1.02-1.07; p=0.001), disseminated malignancy (HR 3.49; 95%CI 1.81-7.86; p=0.004), esophageal varices HR 3.34; 95%CI 1.62-6-64; p=0.001), ischemic heart disease (HR 2.44; 95%CI 1.10-5.19; p=0.023) and a being an inpatient (HR 1.92; 95%CI 1.00-3.98; p=0.042) were independent risk factors for the outcome.

Conclusion

Despite increased comorbidities and older age, patients with AUGIB on ATs had lower in-hospital mortality, with no differences in other relevant outcomes. In fact, our results suggest that AT treatment provides a survival benefit, possibly related to a higher risk of bleeding in milder lesions.
Regarding delayed mortality, it was higher in patients on AT, determined by the comorbidity leading to their prescription.
Interestingly, early resumption of AT was associated with higher in-hospital mortality, while reintroduction after 7 days increased delayed one.

References

1. Lanas A, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-12 e2.
2. Chan FK, Leung Ki EL, Wong GL, et al. Risks of Bleeding Recurrence and Cardiovascular Events With Continued Aspirin Use After Lower Gastrointestinal Hemorrhage. Gastroenterology 2016;151:271-7.
3. Gralnek IM, Stanley AJ, Morris AJ, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy 2021;53:300-332.
4. Dunne PDJ, Laursen SB, Laine L, et al. Previous Use of Antithrombotic Agents Reduces Mortality and Length of Hospital Stay in Patients With High-risk Upper Gastrointestinal Bleeding. Clin Gastroenterol Hepatol 2019;17:440-447 e2.
5. Marmo R, Occhipinti V, Zullo A, et al. Improved Survival for Patients With Acute Upper Gastrointestinal Bleeding While on Antithrombotic Therapy: A Multicenter Prospective Cohort Study. J Clin Gastroenterol 2023;57:278-284.

Introduction

A global surge in anticoagulant use raises concerns about managing acute upper gastrointestinal bleeding (AUGIB) in affected patients.

Aims & Methods

This study presents findings from a large UK multicenter study of AUGIB in patients on anticoagulants.A prospective multicenter observational study included adults (>16 years) from 152 UK hospitals with AUGIB between 3 May- 2 Jul , 2022.

Results

Of 5101 AUGIB cases enrolled, 31%(1566) were on anticoagulants – 10%(n=159) warfarin, 58%(n=912) direct oral anticoagulants (DOACs), and 34%(n=530) heparin (prophylactic dose – 76%, therapeutic dose – 18%, and bridging therapy – 2%). The median age was 78 yrs (IQR 68-85), with 58% being new admissions. Anticoagulants were discontinued post-AUGIB in 87%. The major hemorrhage protocol activated for 4%. Transfusion rates were: 59% packed red blood cells, 7% prothrombin complex concentrate (PCC), 5% fresh frozen plasma, 3% platelets, 0.8% cryoprecipitate, and 0.3% fibrinogen. For DOACs (n=912) a reversal agent was needed for 6% (46% - andexanet alfa and 54% -PCC). Glasgow-Blatchford score (GBS) categorized patients into: 3% low-risk(GBS 0-1), 16% medium-risk(2-6), 33% higher-risk(7-11),and 34% very high-risk(≥12). Inpatient endoscopy was performed in 85%(n=1335). Time to endoscopy from presentation was: 0-6 hrs 5%, 6-24 hrs 32%, 24-48 hrs 25%, and >48 hrs 24%. Bleeding etiologies identified (n=798) included: peptic ulceration (49%), esophagitis (26%), varices (8%), portal hypertensive gastropathy (4%), malignancy (7%), and other (27%). Stigmata of recent bleeding observed in 29% (390/1335) of cases, leading to endotherapy in 25% (328/1335). Anticoagulants resumed while in-patient for 46% (613/1335) – 19% within 24 hrs, 14% 24-48 hrs, 9% 48-72 hrs, and 41% >72 hrs after the index endoscopy. 10% (136/1335) had evidence of further in-patient bleeding after the index endoscopy. Overall, 10%(160/1566) had >1 endoscopy, 1% (16) underwent surgery, and 2.8% (44) had interventional radiology. Median length of stay was 7 days (IQR 4-13), with in-patient mortality at 13%(211). A multivariable logistic regression revealed delayed endoscopy (>48 hrs) was associated with reduced rebleeding odds (OR:0.19,95%CI:0.04-0.99), while early endoscopy (0-6 hrs) was linked to higher rebleeding odds (OR:1.81,95%CI:0.44-7.46).Importantly, stigmata of recent bleeding on endoscopy significantly elevated rebleeding odds (OR:4.88,95%CI:1.75-13.64), emphasizing its prognostic relevance in AUGIB.

Conclusion

A third of AUGIB patients in this multi-center UK study were on anticoagulants at the time of presentation. Real-world evidence underscores the importance of appropriate resuscitation and careful restarting of the anticoagulants based on the indication. Further development of predictive models to guide the time to restart different anticoagulants is needed.

Introduction

Pediatric Acute Liver Failure (PALF) presents a considerable threat to children with a high risk of mortality, despite its rarity. However, the exact cause remains unknown in about half of the cases, emphasizing the need for continued investigation and advancements in our understanding of the condition. Recurrent Acute Liver Failure (RALF) represents an even more uncommon phenomenon, defying diagnosis despite thorough examination. The advent of Whole Exome Sequencing offers hope in uncovering its elusive genetic origins, potentially shedding light on specific genetic disorders underlying this condition.

Aims & Methods

This study aimed to report spectrum of Recurrent Acute Liver Failure (RALF) cases and role of Whole Exome Sequencing (WES) in establishing a cause for RALF, during January 2023 – January 2024 in a tertiary care institute.

Results

We report 4 cases of Recurrent Acute Liver Failure (RALF). First case was a 5 year old 1^st born female child of 3^rd degree consanguineous marriage who presented with RALF during febrile episodes at 10 months, 18 months and 5 years. Child had low GGT (19 IU/L) cholestasis initially. Etiological workup for Wilson, infective, metabolic was normal. Provisionally, Fever Associated Infantile Liver Failure (ILFS) was thought. But, Upper GI endoscopy revealed esophageal varices confirming portal hypertension, and liver biopsy revealed- acute on chronic hepatitis with cirrhosis, confirming chronic liver disease, which was in contrast to complete liver function resolution seen in ILFS. Change in gait and expressive language ability was lost from 3 years of age. The child had rigidity, increased deep tendon reflexes, tremor and ataxia on examination. Genetic analysis revealed homozygous (autosomal recessive) likely pathogenic variant of SCYL1 gene mutation leading to Spinocerebellar Ataxia 21.
The second child also presented with RALF at 8 months, 1year and 1.5 years during febrile episodes, with low GGT Cholestasis. WES revealed pathogenic variant of SCYL1 gene mutation leading to Spinocerebellar Ataxia 21. Child died at 1.5years of age.
Third child is a 10 year old girl presented with multiple fever-related RALF since 9 years of age and was asymptomatic in between episodes. As the cause was indeterminate after extensive evaluation, WES was done which revealed novel compound heterozygote mutation in RINT1 gene in exon 8 and 12.
The fourth child is a sibling of third case who succumbed with the first acute liver failure following a febrile episode at 12 years of age.

Conclusion

Understanding the genetic basis of PALF is crucial for accurate diagnosis and management. Genetic testing, including targeted gene sequencing or whole-exome sequencing, can help identify these mutations and provide insights into the underlying causes of PALF in affected individuals. This information is essential for personalized treatment approaches and genetic counseling for families. In addition to metabolic and mitochondrial diseases, mutations in genes related to both cytosolic and mitochondrial pathways—such as NBAS, TRMU, IRAS, MARS, RINT1, and SCYL1—have been implicated in pediatric acute liver failure (PALF).

References

1. Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R, Berutti R, Adam R, Aldrian D, Baric I, Baumann U. Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology. 2024 May 1;79(5):1075-87.
2. Çakır M, İssi F, Güven B, Yakici N, Karaguzel G, Selimoglu A. Rare Causes of Recurrent Acute Liver Failure In Children: Infantile Liver Failure Syndromes. Klinische Pädiatrie. 2023 Jul;235(04):245-9.
3. Youssef, Mariam et al. “CALFAN (Low γ-Glutamyl Transpeptidase (GGT) Cholestasis, Acute Liver Failure, and Neurodegeneration) Syndrome: A Case Report with 3-Year Follow-Up after Liver Transplantation in Early Adulthood.” Case reports in hepatology vol. 2023 3010131. 31 Jul. 2023, doi:10.1155/2023/3010131

Introduction

Peptic ulcer is the most common cause of upper gastrointestinal bleeding (UGB), accounting for about 50 percent of cases. Several scoring systems have been developed for the early and accurate assessment of patients with UGB to predict clinical outcomes, assisting in the management of patients. The Glasgow-Blatchford score (GBS) is currently recommended for risk stratification of UGB in the emergency department, helping triage patients to in-hospital or ambulatory management. GBS includes hemoglobin, urea, heart rate, systolic blood pressure, co-morbidity and symptoms like syncope and melena.

Aims & Methods

Aim: To compare GBS in patients with bleeding peptic ulcer (BPU) infected and non-infected by Helicobacter pylori (HP).
Methods: We conducted a prospective observational study from September 2019 to March 2002, 48 patients with BPU were prospectively evaluated in a tertiary hospital. During emergency endoscopy, two gastric mucosal biopsy samples (one from corpus and one from the antrum) were collected for polymerase chain reaction (PCR) and invasive rapid urease test (RUT). Two hours later, all underwent carbon-13 urea breath test (13C-UBT). Patients were considered HP infected when two or more tests were positive. The clinical data were obtained from the patients´s records immediately before the endoscopy. The Qui-square test and Fisher were used to compare the groups. Written informed consent was obtained from all patients. The study protocol was approved by the local ethical committee.

Results

Mean age was 61.7±17.3 years, 25 (52.1%) presented with melena. Gastric ulcers were the major cause of acute bleeding in 39 (81.3%) and duodenal in 9 (18.8%) patients. Data about blood transfusion (BT), Rockall Score (RS) and presence of blood in the stomach are represented in table 1. GBS was significantly lower in HP positive patients (n=19) compared to HP negative (n=25): 9.1±3.3 e 11.5±3.1, p= 0.0441.

Table 1. Comparison between H.pylori negative and positive groups

* BT: blood transfusion, RS: Rockall score, GBS: Glasgow Blatchford score

Conclusion

H pylori positive patients showed less comorbidities and lower GBS in the BPU scenario. HP negative patients need more severe clinical conditions to bleed than those HP positive. HP is a pathogenic factor by itself, suggesting that GBS might be underestimated in this population. A score using HP presence could be better to predict prognostic in the episode of bleeding peptic ulcer.

References

Bibliography:

1. Akhila Arya PV, Thulaseedharan NK, Raj R, Unnikrishnan DC, Jacob A. AIMS65, Glasgow-Blatchford bleeding score and modified Glasgow-Blatchford bleeding score in predicting outcomes of upper gastrointestinal bleeding: An accuracy and calibration study. Indian J Gastroenterol. 2023 Aug;42(4):496-504. doi: 10.1007/s12664-023-01387-z. Epub 2023 Jun 29. PMID: 37382854.

2. Jang HJ, Lee D, Kim TH, Kim JS, Lee HJ, Kim JB, Kim JY. Clinical outcomes of gastrointestinal bleeding management during anticoagulation therapy. PLoS One. 2022 Jun 3;17(6):e0269262. doi: 10.1371/journal.pone.0269262. PMID: 35658063; PMCID: PMC9165820.

3. Gralnek IM, Stanley AJ, Morris AJ, Camus M, Lau J, Lanas A, Laursen SB, Radaelli F, Papanikolaou IS, Cúrdia Gonçalves T, Dinis-Ribeiro M, Awadie H, Braun G, de Groot N, Udd M, Sanchez-Yague A, Neeman Z, van Hooft JE. 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. doi: 10.1055/a-1369-5274. Epub 2021 Feb 10. PMID: 33567467.

Introduction

Chronic constipation (CC) is a prodromal and severe symptom in up to the 80% of Parkinson's disease (PD) patients (PD/CC) often refractory to standard laxative treatments. The molecular mechanisms underlying PD/CC are still unclear, although changes of enteric nervous system and intestinal epithelial barrier (IEB) have been thought to play a pathogenetic role.

Aims & Methods

In this study, PD/CC and chronic constipated (CCs) patients were functionally characterized, and possible abnormalities to IEB and the key neuromodulator vasoactive intestinal polypeptide (VIP) were investigated. N=12 PD/CCs (2 females; age range: 51-80 yrs), 20 CCs (15 females; 27-78; yrs) and 23 controls (Ctrls; 11 females; 32-74yrs) were enrolled. PD was diagnosed according to the United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic criteria, whereas CC was established following Rome IV criteria. Ctrls were otherwise asymptomatic subjects undergoing screening colonoscopy. Ten PD/CCs and 10 CCs were functionally characterized by anorectal manometry (AM) and transit time (TT). Colonic mucosal / submucosal biopsies were obtained in all patients / subjects and tested for gene, protein expression and localization of IEB tight junction markers claudin-4 (CLDN4), occludin-1 (OCCL-1) and zonula occludens-1 (ZO-1) and VIP, by RT-qPCR, immunoblot and immunofluorescence staining.

Results

PD/CCs were clustered in two groups: a) patients with delayed TT and altered AM (60%); b) those with altered AM only (13%). The evaluation of IEB markers on mucosal specimens showed an increase of CLDN4 mRNA in PD/CCs (1.26 ± 0.26) vs. Ctrls (1.00 ± 0.19) and CCs (0.95 ± 0.33), whereas a trend to CLDN4 protein reduction in PD/CCs (0.88 ± 0.33) vs. Ctrls (0.96 ± 0.25) and CCs (1.02 ± 0.51) was observed. Moreover, the OCCL-1 transcript was significantly increased in PD/CCs (1.36 ± 0.36) vs. Ctrls (1.05 ± 0.33) and CCs (0.81 ± 0.18). ZO-1 mRNA relative levels were consistent with those of OCCL-1 showing a significant increase in PD/CCs (1.35 ± 0.38) vs. Ctrls (1.02± 0.27) and CCs (0.85 ± 0.24). Notably, both OCCL-1 and ZO-1 showed a tendency to be reduced in CCs vs. Ctrls. Immunofluorescence highlighted a decrease in OCCL-1 immunoreactivity (IR) in PD/CCs (score= 1.5) vs. CCs and Ctrls (score= 4). Conversely, ZO-1-IR displayed an intense pattern (score=4) in both Ctrls and PD/CCs, but it was decreased in CCs (score= 2). VIP mRNA levels resulted significantly greater in CCs (3.98 ± 3.93, p<0.05) vs. Ctrls (1.52 ± 1.55) and PD/CCs (0.86 ± 1.056), whereas a decreasing trend was observed in PD/CCs vs. Ctrls (p>0.05). Both immunofluorescence and immunoblot confirmed this tendency showing a 15% drop of the VIP protein (PD/CCs 0.86 ± 0.43 vs. Ctrls 1.01 ± 0.56, p>0.05).

Conclusion

Transit and anorectal dysfunctions in PD/CCs are associated with ZO-1, OCCL-1, CLDN-4 and VIP changes, hence suggesting that a leaky IEB contributes to submucosal neurochemical abnormalities underlying PD/CC. These findings suggest that the expression of the IEB markers are subject to both transcriptional and post-translational regulatory mechanisms, presumably distinct in CC and PD/CC.

References

1. Giancola F, Torresan F, Repossi R, Bianco F, Latorre R, Ioannou A, Guarino M, Volta U, Clavenzani P, Mazzoni M, Chiocchetti R, Bazzoli F, Travagli RA, Sternini C, De Giorgio R. Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation. Neurogastroenterol Motil. 2017 May;29(5):10.1111/nmo.12995.
2. Clairembault T, Leclair-Visonneau L, Coron E, Bourreille A, Le Dily S, Vavasseur F, Heymann MF, Neunlist M, Derkinderen P. Structural alterations of the intestinal epithelial barrier in Parkinson's disease. Acta Neuropathol Commun. 2015 Mar 10;3:12.
3. Neunlist M, Toumi F, Oreschkova T, Denis M, Leborgne J, Laboisse CL, Galmiche JP, Jarry A. Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways. Am J Physiol Gastrointest Liver Physiol. 2003 Nov;285(5):G1028