Introduction

The gut-liver axis, the anatomical and physiological connection between the gut and liver, is hypothesized to contribute to the development of portal vein thrombosis (PVT) in patients with end-stage liver disease (ESLD). It has been proposed that the portal vein in patients with ESLD is an inflammatory vascular bed due to the translocation of endotoxins and proinflammatory cytokines from the gut. We hypothesized that a pro-inflammatory gut microbiome in ESLD patients, and elevated levels of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) which is an established driver of thrombosis, may contribute to the development of PVT.

Aims & Methods

In this cross-sectional study we investigated whether differences in gut microbiome diversity, bacterial species, metabolic pathway abundances, and TMAO blood levels are associated with presence of PVT in ESLD patients. Fecal samples, serum samples and data from patients with ESLD, as well as living kidney transplant donors (‘healthy controls’), were collected from the TransplantLines Biobank and Cohort Study (NCT02811835). PVT was defined as presence of a thrombus in the portal vein assessed by either radiology or during surgery within a year prior to or after fecal sample collection. We analyzed the fecal samples using Shotgun Metagenomic Sequencing to assess and compare microbiome diversity, microbial taxonomy, and metabolic pathways abundances. TMAO levels were measured in serum samples using a Vantera® Clinical Analyzer (LabCorp, Morrisville, NC, USA).

Results

A total of 102 ESLD patients, of which 23 had PVT, and 246 healthy controls were included. We found no significant difference in microbiome diversity between patients with PVT (median Shannon Diversity Index (SDI): 2.08), and without PVT (median SDI: 1.84; P=0.18). Both ESLD groups had lower microbiome diversity compared to healthy controls (median SDI: 2.55; both P<0.05). A Beta Diversity Analysis confirmed that the gut microbiome of ESLD patients was markedly distinct from that of healthy controls. After false discovery rate correction, Bacteroides fragilis and three species from the family Clostridiales were increased in abundance in ESLD patients with PVT compared to those without PVT. No altered metabolic pathways abundances were observed between both ESLD groups. Overall, altered abundances of 29% (n=49) and 51% (n=86) bacterial species, and 18% (n=96) and 35% (n=191) metabolic pathways were observed between patients with and without PVT, respectively, when compared to healthy controls. TMAO levels were higher in both ESLD patients with (3.30µm) and without PVT (3.00µm) compared to healthy controls (2.70µm) (P = 0.13 and P = 0.84 respectively), with a trend towards higher levels in patients with PVT (P = 0.19).

Conclusion

Although we observed a profound difference in gut microbiota composition between patients with ESLD and healthy controls, our analysis revealed minimal differences in the gut microbiome composition between ESLD patients with or without PVT. These results indicate that a gut microbiome-derived pro-inflammatory state was not associated with the presence of PVT in these patients.

Introduction

Advanced chronic liver disease (ACLD) may present in different stages with distinct prognoses. Child-Pugh and MELD scores are commonly used models for predicting liver-related mortality and decompensation, but they have several limitations. An alternative or complementary tool that is simple and cost-effective would be invaluable. Recently, some studies identified a potential role of ammonia in predicting liver-related outcomes.

Aims & Methods

Our primary objective was to explore the predictive role of plasma ammonia levels regarding liver-related complications and mortality. Our secondary aim was to validate a new measure that corrects baseline ammonia levels to the upper limit of normal (AMM-ULN) and test a cut-off which was proposed in the literature to define patients at higher risk of such outcomes (AMM-ULN ≥ 1.4).
This retrospective study included 278 patients with ACLD who had an ammonia measurement in our hospital between 2018 and 2022. ACLD patients were divided into compensated and decompensated stages, with the latter being subdivided into three stages, according to the type of decompensation. Outcomes of liver-related decompensation and mortality were assessed in each group. AMM-ULN was evaluated as a predictor of these outcomes both in compensated and decompensated patients. The predictive accuracy of AMM-ULN was then determined by identifying the best cut-off.

Results

Plasma ammonia levels and AMM-ULN were predictors of hepatic decompensation (HR = 1.453, 95%CI 1.085 – 1.945, p = 0.012) and mortality (HR = 1.010, 95%CI 1.003 – 1.017, p < 0.001) at 12 months, in the compensated patient group. The AUROC for AMM-ULN was 67.4% in 1-year decompensations and 69.5% in 1-year mortality, with similar results for ammonia levels. AMM-ULN ≥ 1.4 identified patients at higher risk of liver-related decompensation and mortality at 12 months (p = 0.009 and p = 0.020, respectively).

Conclusion

Both ammonia levels and AMM-ULN were predictors of hepatic decompensation and liver-related mortality in compensated patients, at 12 months of follow-up. AMM-ULN ≥ 1.4 identified patients at higher risk of liver-related decompensation and mortality at 12 months.

References

D’Amico, G., Garcia-Tsao, G., & Pagliaro, L. (2006). Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. Journal of Hepatology, 44(1), 217–231. https://doi.org/10.1016/j.jhep.2005.10.013
Haj, M., & Rockey, D. C. (2018). Predictors of clinical outcomes in cirrhosis patients. Current Opinion in Gastroenterology, 34(4), 266–271. https://doi.org/10.1097/MOG.0000000000000450
De Franchis, R. et al (2022). Baveno VII – Renewing consensus in portal hypertension. Journal of Hepatology, 76(4), 959–974. https://doi.org/10.1016/j.jhep.2021.12.022
Shalimar, Sheikh, M. F. et al (2019). Prognostic Role of Ammonia in Patients With Cirrhosis. Hepatology, 70(3), 982–994. https://doi.org/10.1002/hep.30534
Tranah, T. H. et al (2022). Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis. Journal of Hepatology, 77(6), 1554–1563. https://doi.org/10.1016/j.jhep.2022.07.014
Balcar, L. et al (2023). Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease. JHEP Reports, 5(4), 100682. https://doi.org/10.1016/j.jhepr.2023.100682
Elzeftawy, A. et al (2018). Evaluation of the blood ammonia level as a non-invasive predictor for the presence of esophageal varices and the risk of bleeding. The Turkish Journal of Gastroenterology. https://doi.org/10.5152/tjg.2018.17894

Introduction

Upper gastrointestinal bleeding (UGIB) is one of the main potentially life-threatening emergencies encountered in gastroenterology that requires prompt management. For this reason, numerous prognostic scores have been developed to predict the level of risk in patients. However, there are few studies in the literature comparing these scores.

Aims & Methods

The main objective of this study was to compare the performance of the pre-endoscopic scores Glasgow-Blatchford Score (GBS), Rockall Score (pRS), and quick Sequential Organ Failure Assessment (qSOFA) in predicting the severity of UGIB according to predefined criteria.
Methods: This is a retrospective descriptive and analytical study of 102 patients who presented with upper gastrointestinal bleeding at the International University Hospital Cheikh Khalifa over a period of 1 year between October 2021 and October 2022. Scores were calculated for each patient with complete medical records. The data was analyzed using the Jamovi 2.2.5 software. The accuracy of each risk score in predicting clinical criteria was evaluated by the area under the receiver operating characteristic curve (AUROC). A p-value less than 0.05 was considered statistically significant.

Results

The included patients had a mean age of 57.1 years with a slight female predominance (53.9%). GBS was found to be more predictive of the risk of admission to the Intensive care Unit (ICU) and the need for blood transfusion than pRS and qSOFA with an AUROC of 0.914 for these two criteria. GBS was also more predictive of the risk of therapeutic intervention (AUROC 0.882) compared to pRS (AUROC 0.788) and qSOFA (AUROC 0.676). Regarding endoscopic intervention, pRS and GBS were equally able to predict this criterion with moderate power (AUROC pRS 0.721) (AUROC GBS 0.747). qSOFA showed no significant performance, especially in its preferred domain of admission to the ICU (AUROC 0.735) (Table). None of the 3 scores was able to predict the need for surgical intervention.

Table: Comparison of AUC, sensitivity, specificity, PPV and NPV along with cut-off value of Glasgow-Blatchford Score, pre-Rockall, and Quick-Sofa scores to predict the clinical outcomes

Conclusion

At the end of this study, the use of GBS and pRS in daily clinical practice in emergency departments is strongly recommended to predict the need for therapeutic intervention, hospitalization, or re-bleeding episodes. However, it would be interesting to study the usefulness of these prognostic scores, especially qSOFA, through larger prospective studies.

References

1. Cúrdia Gonçalves T, Barbosa M, Xavier S, et al. Optimizing the Risk Assessment in Upper Gastrointestinal Bleeding: Comparison of 5 Scores Predicting 7 Outcomes. GE Port J Gastroenterol. nov 2018;25(6):299‑307.
2. Tham J, Stanley A. Clinical utility of pre-endoscopy risk scores in upper gastrointestinal bleeding. Expert Rev Gastroenterol Hepatol. déc 2019;13(12):1161‑7.
3. Aquarius M, Smeets FGM, Konijn HW, et al. Prospective multicenter validation of the Glasgow Blatchford bleeding score in the management of patients with upper gastrointestinal hemorrhage presenting at an emergency department. Eur J Gastroenterol Hepatol. sept 2015;27(9):1011‑6.
4. Li Y, Lu Q, Song M, Wu K, Ou X. Comparisons of six endoscopy independent scoring systems for the prediction of clinical outcomes for elderly and younger patients with upper gastrointestinal bleeding. BMC Gastroenterol. 13 avr 2022;22(1):187
5. Renukaprasad AK, Narayanaswamy S, R V. A Comparative Analysis of Risk Scoring Systems in Predicting Clinical Outcomes in Upper Gastrointestinal Bleed. Cureus. juill 2022;14(7):e26669
6. Taslidere B, Sonmez E, Özcan AB, Mehmetaj L, Keskin EB, Gulen B. Comparison of the quick SOFA score with Glasgow-Blatchford and Rockall scores in predicting severity in patients with upper gastrointestinal bleeding. Am J Emerg Med. juill 2021;45:29‑36

Disclosure

All co-authors have seen and agree with the contents of the manuscript and there is no conflict of interest.

Introduction

Congenital Diarrhea and Enteropathies (CODEs) pose significant challenge for diagnosis and management. Genetic sequencing for children with CODEs has important implication in early diagnosis.

Aims & Methods

Among children with chronic diarrhea those suspected to have CODEs clinically and endoscopically during the period of March 2023 to Feb 2024 were included.
Clinical profile, endoscopic, histological and genetic analysis were studied in all children with suspected CODES.

Results

Total 15(n=15) cases were included. Overall male preponderance 80%(n=12) was noted. Age at onset ranged from 2days of life to 15months with mean age of 4months. Of them, 10(66%) children had watery diarrhea, 4(26%) children had bloody diarrhea and 1(6.6%) child had fatty diarrhea.
Endoscopic and histological yield in CODES children were found in 40%(n=4) and 30%(n=3) respectively in children with watery diarrhea, and in all children with fatty or bloody diarrhea.
Out of 10 children with watery diarrhea two children had syndromic facies, woolly hair and café-u-lait spots were diagnosed as Syndromic Diarrhea-Trichohepaticoenetric Syndrome(THES). 3 of them had protein losing enteropathy(PLE) with two among 3 showing normal endoscopy and biopsy,finally turned out to be enterokinase deficiency, while one child with endoscopically viewed whitish speckled mucosa with patchy vacuolated surface on histology had DGAT 1 mutation. Two children with watery diarrhoea had microvillous atrophy(MYO5B) and one with severe watery diarrhea had NEUROG3 mutation. Glucose galactose malabsorption (GGM), and Congenital Tufting Enteropathy (CTE) were seen in other two children. Among children with bloody diarrhea, two had proctocolitis on histology confirming Very Early Onset Inflammatory Bowel Disease(VEO-IBD) with genetic mutation showing CARMIL 2 and RIPK1 mutation. Two children with bloody diarrhoea suspected to have IBD had chronic colitis with thrombotic complications suggesting CD55 deficiency with Hyperactivation of complement, Angiopathic thrombosis, and PLE (CHAPLE syndrome). child with fatty diarrhoea with endoscopic findings suggestive of intestinal lymphangiectasia and histology of duodenal biopsy showing lipid droplets was clinically and genetically diagnosed Abetalipoproteinemia and started on fat free diet with MCT oil and vitamin A,D,E,K supplements. Genomic analysis are the final stand of diagnosing CODES due to the overlap of the clinical phenotypes and lack of appropriate biomarkers.Genetic Analysis had 100% yield when CODES were suspected. Overall mortality rate was 26%(n=4) in 1year follow-up in our study group.

Conclusion

Single gene disorders are common among CODEs patients. Early Genetic testing helps in accurate diagnosis and initiating appropriate therapy as endoscopy and histology has poor yield.

References

•Lee, Kun Song et al. “How to do in persistent diarrhea of children?: concepts and treatments of chronic diarrhea.” Pediatric gastroenterology, hepatology & nutrition vol. 15,4 (2012): 229-36. doi:10.5223/pghn.2012.15.4.229
•Thiagarajah, Jay R et al. “Advances in Evaluation of Chronic Diarrhea in Infants.” Gastroenterology vol. 154,8 (2018): 2045-2059.e6. doi:10.1053/j.gastro.2018.03.067
•Bourgeois, P., Esteve, C., Chaix, C., Beroud, C., Levy, N., THES Clinical Consortium, Fabre, A., Badens, C. Tricho-hepato-enteric syndrome mutation update: mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects. Hum. Mutat. 39: 774-789, 2018

Introduction

Mucinous cysts of the pancreas are known precursors of pancreatic ductal adenocarcinoma. International guidelines for management and surveillance of pancreatic cysts advise surgical resection of high-risk lesions - mucinous cystic neoplasms (MCNs) and main duct intraductal papillary neoplasms (IPMNs), especially in those with worrisome clinicopathological stigmata. For low-risk cysts, lifelong radiographic surveillance is the standard approach, which can be psychologically distressing for patients and burdensome for healthcare systems. Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) of high-risk cystic lesions of the pancreas is increasingly being used as a minimally invasive alternative in patients who are unfit for or who decline surgery (1). We assessed the safety and efficacy of EUS-guided RFA in the management of low-risk cystic lesions of the pancreas.

Aims & Methods

68 patients (29M, 39F; mean age 63, range 33-82 years) with low-risk mucinous cystic neoplasms of the pancreas (branch-duct IPMN/mucinous cystadenomas, 0.7-4cm in size) were recruited for treatment by EUS-RFA. The primary endpoint was change in size of the pancreatic cyst on cross-sectional imaging (MRI) at one year after treatment (efficacy). Secondary endpoints included progression following treatment, procedure related morbidity and local complication rate (safety).

Results

68 patients were recruited of whom 55 completed RFA ablation of their cyst. Anatomical concerns (i.e., blood vessel, main duct proximity) precluded RFA in 12 patients. 18/55 patients (33%) underwent a second ablation. Follow up imaging data were available for 46 (84%) patients and showed a <20% reduction in cyst size in 18 patients, 20-49% in 4 patients, 50-79% in 5 and 80-100% size reduction in 18 patients. For one patient, doubling in cyst size was recorded at the 12-month follow-up. Excluding one case of scope-induced small bowel perforation (Clavien-Dindo; ClvD grade 3), other adverse events were mild (ClvD 0-2) and expected (transient abdominal pain, bloating, sore throat, nausea/vomiting). One patient experienced a self-limiting, post procedure grand mal seizure on a background of epilepsy.

Conclusion

​EUS-RFA was well tolerated in most cases. Our data indicate that the procedure is relatively safe. The response ranged from a <20% reduction in size to complete cyst resolution.

References

1. Papaefthymiou A, Johnson GJ, Maida M, Gkolfakis P, Ramai D, Facciorusso A, Arvanitakis M, Ney A, Fusai GK, Saftoiu A, Tabacelia D, Phillpotts S, Chapman MH, Webster GJ, Pereira SP. Performance and safety of EUS-ablation techniques for pancreatic cystic lesions: a systematic review and meta-analysis. Cancers 2023 [in press].

Disclosure

No conflict of interest

Clinical Case Summary

A 40-year-old male came to our emergency department referring worsening jaundice, mental status deterioration, epigastric pain and anorexia over the past week. Four weeks earlier he presented odynophagia, myalgias, and hand pruritus but didn’t seek medical attention.
Patient’s clinical background included cognitive impairment due to peripartum anoxia and type 2 Diabetes Mellitus. At admission, he had elevated liver enzymes (R value=2,7), coagulopathy (INR 1.3), pancreatic enzymes >3 times the upper normal level and hyperbilirubinemia (mostly conjugated).
The CT-scan revealed pancreatic tail globosity, diffuse abdominal and retroperitoneal peri-centimetric lymph nodes and excluded biliary lithiasis.
After common causes of acute hepatitis and pancreatitis were ruled out, and since patient was at risk of acute liver failure despite supportive treatment, a liver biopsy was performed. Autoimmune hepatitis, drug-induced liver injury or lymphoproliferative disease were held as potential differentials. Hepatitis E Virus (HEV) RNA was then found and genotyped in the serum (genotype 3). HEV infection was assumed as the cause for both hepatitis and pancreatitis. Histological pattern was inconclusive and epidemiological source wasn’t found.

HEV infection paradigm has changed and is now considered an endemic zoonotic infection in most high-income countries (Portuguese seroprevalence is 16.3%)¹. Infection occurs due to ingestion of undercooked pig or boar meat and should be suspected in every acute hepatitis, mostly with a cholestatic pattern.
The setting of acute HEV hepatitis complicated with acute pancreatitis (AP) is uncommon². AP usually starts after a median of 10 days of jaundice onset³. Literature only reports association between AP and HEV caused by genotype 1 from Southeast Asia^{3 4}, and genotype 3 was only related to gallstone-related pancreatitis, according to current knowledge⁵. This might be the first form of HEV genotype 3 infection with hepatitis and pancreatitis.

References

1. Nascimento MSJ, Pereira SS, Teixeira J, et al. A nationwide serosurvey of hepatitis E virus antibodies in the general population of Portugal. Eur J Public Health 2018;28(4):720-24. doi: 10.1093/eurpub/ckx213 [published Online First: 2017/12/14]
2. Debnath P, Datta AK, Chakraborty U, et al. Acute viral hepatitis E complicated with acute pancreatitis in an immunocompetent adult. BMJ Case Rep 2021;14(2) doi: 10.1136/bcr-2020-239684 [published Online First: 2021/02/06]
3. Haffar S, Bazerbachi F, Garg S, et al. Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review. Pancreatology 2015;15(4):321-6. doi: 10.1016/j.pan.2015.05.460 [published Online First: 2015/06/08]
4. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018;68(6):1256-71. doi: 10.1016/j.jhep.2018.03.005 [published Online First: 2018/04/04]
5. Karlsson M, Norder H, Bergstrom M, et al. Hepatitis E virus genotype 3 is associated with gallstone-related disease. Scand J Gastroenterol 2019;54(10):1269-73. doi: 10.1080/00365521.2019.1666163 [published Online First: 20190925]