Introduction

Gastroesophageal reflux disease (GERD) patients with atypical symptoms represents a diagnostic and therapeutic challenge. In particular, the diagnosis of GERD is often suspected by ENT surgeons according to laryngoscopic findings, but their sensitivity and specificity for diagnosis is low. The aim of this study was to assess the prevalence of GERD in patients with atypical symptoms undergoing laryngoscopic examination and pH monitoring.

Aims & Methods

We retrospectively evaluated patients with atypical symptoms with or without typical symptoms associated referred to Gastroenterology Units of six tertiary Italian centres between January and December 2020. Of 477 patients, we enrolled 277 patients who underwent both 24 hours pH-impedance monitoring off-therapy and laryngoscopy. Diagnosis of GERD was made according to Lyon Consensus, and we considered the novel impedance metrics (baseline impedance and post reflux swallow-induced peristaltic wave index) when pH-impedance monitoring was inconclusive in order to add confidence to diagnosis of GERD. Three patients with hypersensitive esophagus were excluded.

Results

The most common atypical symptom was cough (90/274). Laryngoscopic examination showed pathological findings in 195 patients (71.2%), and the most frequent feature detected was posterior laryngitis (77.4%). GERD was diagnosed in 80/274 patients (29.2%) on pH impedance monitoring. Upper endoscopy was made in 269 patients and 5 of them had B grade esophagitis. The prevalence of GERD diagnosis in patients with or without positive laryngoscopy examination was not statistically significant (p=0.075). No difference in the number of proximal refluxes was observed in patients with positive or negative laryngoscopy (65/195, 33.3% vs 19/79, 24.1%; p= 0.133). Sensitivity and specificity of laryngoscopy in diagnosing GERD is 78.8% and 32.0% respectively (PPV= 32.3%; NVP= 28.4%).

Conclusion

Laryngoscopic examination has a poor specificity in diagnosing GERD in patients with atypical symptoms. This study may underline that pathological laryngoscopy findings could only pose a suspect of an underlying GERD, but its diagnosis would still need to be confirmed by impedance-pH monitoring, even in patients with atypical symptoms.

Introduction

Eosinophilic oesophagitis (EoE) is a chronic, progressive type 2 inflammatory disease. Proton-pump inhibitors (PPIs), swallowed topical corticosteroids (STCs), and elimination diets have been used as standard treatments for EoE patients. However, the real-world evidence (RWE) highlighting disease burden in Europe are limited.

Aims & Methods

To assess disease burden and treatment patterns among adolescent and adult patients with EoE in real-world practice.
Medical records were retrospectively reviewed for patients (aged ≥12 years) who were newly diagnosed with EoE between 1 January 2009 and 31 December 2019 (index) in Germany, France, Spain, and the United Kingdom. Patients with a peak eosinophil (eos) count (PEC) of ≥15 eos/hpf within 90 days of the index date and ≥1 follow-up endoscopy within 24 months of the index date were included. Demographics, clinical features, treatment patterns, and health outcomes were assessed from the 12-month pre-index period to the last medical record entry or death. Disease progression was assessed via physician-defined (based on symptoms, endoscopy findings, histology, need for dilation, and food impaction) and proxy-reported outcomes (dilation performed, strictures, dysphagia, evidence of food impaction, treatment initiation in treatment-naïve patients and switching/augmentation).

Results

Overall, 385 patients were included, with 70.1%–78.1% being male; the mean age was 27.8 to 33.9 years. At EoE diagnosis, the PEC was 35.3–46.1 eos/hpf, the endoscopic appearance of the oesophagus was abnormal in 73.7%–85.6% of patients, and dysphagia was present in 59.8%–82.8% of patients. Most of the patients across all 4 countries were treated with PPIs (61.5%–91.8%), STCs (56.7%–82.3%) and elimination diets (41.4%–55.2%) after EoE diagnosis. Of the patients with available data, abnormal histology (≥15 eos/hpf) was reported in 44.8%–72.0% of patients during the first 5 years after EoE diagnosis. The abnormal endoscopic appearance of the oesophagus was observed in 34.6%–83.3% of patients after approximately 2 years of EoE diagnosis and dysphagia was present in 10.2%–25.0% of patients after 4 years of EoE diagnosis across all 4 countries. While physician-defined disease progression occurred in 6.1%–16.1% of patients, 19.4%–35.1% of patients experienced proxy-reported outcomes of potential disease progression (including oesophageal dilation performed in 10.8%–21.7% of patients) after EoE diagnosis. An overview of patient and clinical characteristics at EoE diagnosis and treatment patterns and disease progression (physician-defined and proxy-reported) after EoE diagnosis across Germany, France, Spain, and the United Kingdom is provided in the Table.

Conclusion

Adolescent and adult patients with EoE chronically experienced substantial disease burden. A subset demonstrated disease progression, perhaps underrecognised despite treatment with PPIs, STCs, and elimination diets. Hence, successful EoE management may include proactive disease monitoring, treating underlying pathophysiology and prescribing maintenance therapies to achieve long-term clinical remission.

References

​

Disclosure

Ulrike von Arnim: Consulting and/or speaker fees from Dr. Falk Pharma, Sanofi, Astra Zeneca, EsoCap, Abbvie, Janssen, Takeda, Pfizer, Bristol Myers Squibb.
Frank Zerbib: Consulting and/or speaker fees from Sanofi, Dr Falk pharma, Bristol Myers Squibb, Bioprojet, AstraZeneca.
Tiffany Pela, Juby A. Jacob-Nara, Gaelle Le-Bagousse-Bego, Sarette T. Tilton: Employees of Sanofi; may hold stocks and/or stock options in the company.
Bram P. Raphael, Amr Radwan, Ryan B. Thomas: Employees of Regeneron Pharmaceuticals, Inc.; may hold stocks and/or stock options in the company.
Rohan C. Parikh, Fareedat Bello: Employees of RTI Health Solutions, which received research funding from Sanofi to design and execute this study.
Funding: This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
Acknowledgement: Medical writing support was provided by Akshata Rao and Ali Nasir Siddiqui, PhD, of Sanofi.

Introduction

The impact of achieving endoscopic remission in ulcerative proctitis (UP) is unclear. The preferred long-term treatment goal in ulcerative colitis (UC) is achieving both the symptomatic resolution and endoscopic remission (ER),¹ which has been associated with reduced risk of complications, including colectomy.^2,3 UP is an anatomically limited form of UC, involving only the rectum. Unlike in extensive or left-sided UC, UP has not been associated with elevated colorectal cancer risk. Therefore, the achievement of endoscopic healing as compared to clinical remission in UP represents an uncertain therapeutic target.⁴

Aims & Methods

This study assessed the impact of achieving EH on subsequent outcomes in UP patients. This was a single-center retrospective cohort study including patients aged ≥ 18 with a confirmed diagnosis of UP based on clinical and endoscopic criteria. Included patients had at least two endoscopies and active endoscopic disease (Mayo endoscopy score [(MES) of 1, 2, or 3]) at the first (baseline) endoscopy. EH was defined as an MES of 0 or 1 at the second (follow-up) procedure. A minimum time of 1 month between scopes was required for inclusion. Descriptive statistics were used for baseline characteristics. The relationship of EH to IBD-related outcomes was assessed using univariate analysis (Pearson's Chi-squared test; Fisher's exact test; Welch Two Sample t-test) and we identified those independently associated with EH using multivariable logistic regression analysis (odds ratio with 95% confidence interval).

Results

Among 200 UP patients with baseline endoscopic activity, 109 patients (54.5%) achieved EH at follow-up. The median time from baseline to follow-up was 15 months (IQR: 6, 31). EH at follow-up was significantly associated with fewer IBD-related ED visits (healing: 8.3%, no healing: 21%) or hospitalizations (5.5% vs 18%) and fewer GI visits (mean: 8 [SD: 9], vs 17 [22]) after the second scope. Patients with EH were less likely to have iron deficiency anemia (IDA; 23% vs 41%), iron infusion (10% vs 25%), C. difficile infection (0.9% vs 6.6%), or to initiate a new biologic after relapse (15% vs 33%). Patients with EH also had a greater time to clinical relapse (650 days [730] vs 270 days [416]). In multivariable analysis, patients with mucosal healing had 68% lower odds of an IBD-related ED visit (OR: 0.32, 95% CI: 0.13, 0.73), 74% lower odds of IBD-related hospitalization (0.26 [0.09, 0.67]), and 64% lower odds of biologic initiation after relapse (0.36 [0.13, 0.95]) compared to patients with no mucosal healing, adjusting for the index MES score.

Conclusion

UP patients with endoscopic healing had less IBD-related healthcare utilization (ED visits, hospitalizations, GI visits), fewer IBD-related complications (IDA, iron infusion, C. difficile infection), and were less likely to escalate to biologics after relapse. Our findings suggest that using a treatment target of endoscopic healing is desirable in UP and shed light on its potential utility in preventing disease-related complications and improving long-term outcomes.

References

1. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Off J Am Coll Gastroenterol ACG. 2015;110(9):1324-1338. doi:10.1038/ajg.2015.233
2. Colombel JF, Rutgeerts P, Reinisch W, et al. Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis. Gastroenterology. 2011;141(4):1194-1201. doi:10.1053/j.gastro.2011.06.054
3. Impact of mucosal healing on long‐term outcomes in ulcerative colitis treated with infliximab: a multicenter experience - Laharie - 2013 - Alimentary Pharmacology & Therapeutics - Wiley Online Library. Accessed September 24, 2022. https://onlinelibrary.wiley.com/doi/full/10.1111/apt.12289
4. Zhou Q, Shen ZF, Wu B sheng, et al. Risk of Colorectal Cancer in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis. Gastroenterol Res Pract. 2019;2019:1-11. doi:10.1155/2019/5363261

Disclosure

E.L., A.A.: no conflicts of interest to disclose
R.B.: Consulting/Speaker: Janssen, Abbvie, Bristol Myers Squibb, Prometheus Laboratories, Pfizer, Takeda
R.L.: Consulting/Speaking Fees: Pfizer, Enzymetrics, Ancilia Biosciences. Grant Support: National Institute of Health (NIH)
E.S.: Consulting/Speaking Fees: AbbVie, Crohn’s and Colitis Foundation of America (CCFA), Entera Health, Evidera, GI Health Foundation, Janssen, Protagonist Therapeutics, Seres Health, Takeda Pharmaceuticals, Bristol Myers Squibb. Grant Support: Abbott (AbbVie), AstraZeneca, CCFA, Janssen Research & Development, Johns Hopkins University, National Institute of Diabetes and Digestive and Kidney (NIDDK), National Institute of Health (NIH), New York Crohn’s Foundation, Pfizer, UCB, UCSF–CCFA Clinical Research Alliance, Genentech, Seres Therapeutics, Celgen. R.B.: Consulting: Prometheus
D.L.: Consulting/Speaking Fees: Abbvie, Boehringer Ingelheim, Eli Lilly, Fresenius Kabi, Janssen, Palatin, Pfizer, Prometheus Biosciences, Takeda; Grants: Abbvie, Janssen, Takeda

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

Vonoprazan (VPZ)-based regimens are an effective first-line therapy for Helicobacter pylori infection. However, their value as a rescue therapy needs to be explored.

Aims & Methods

We assessed a VPZ-based regimen as a H. pylori rescue therapy.
Patients with a history of H. pylori treatment failure were administered 20 mg VPZ twice daily, 750 mg amoxicillin 3 times daily, and 250 mg Saccharomyces boulardii twice daily for 14 days. ¹³C-urea breath tests were used to assess H. pylori status; adverse events were recorded using a questionnaire.

Results

We enrolled 68 patients with 1–3 previous eradication failures. The overall eradication rates calculated using intention-to-treat and per-protocol analyses were 92.6% (63/68) and 92.3% (60/65), respectively. The eradication rate did not differ with the number of treatment failures. The rates of clarithromycin, metronidazole, and levofloxacin resistance were 91.3% (21/23), 100% (23/23), and 60.9% (14/23), respectively. In 60.9% (14/23) patients, the H. pylori isolate was resistant to all 3 antibiotics. The eradication rate was higher among patients without anxiety (96.8%) than among patients with anxiety (60.0%, P = 0.025). No severe adverse events occurred; 95.6% (65/68) patients showed good compliance. Serological examination showed no significant changes in liver and kidney function.

Conclusion

Vonoprazan and amoxicillin dual regimen with S. boulardii supplementation is a safe and effective H. pylori rescue therapy, with an acceptable eradication rate (>90%), regardless of the number of prior treatment failures. Anxiety was associated with eradication failure, and the regimen may need to be adjusted for patients with anxiety.

Introduction

Inflammatory bowel disease (IBD), comprising of Crohn’s disease and Ulcerative Colitis (UC), is a debilitating inflammatory disease of the gastrointestinal tract with no known cause. Although extensive work has linked numerous genetic loci to IBD, most of these associations remain poorly understood. In addition, some studies have associated IBD to metabolic diseases such as diabetes and non-alcoholic fatty liver disease (NAFLD), although the precise molecular and pathophysiological mechanisms underlying these associations are unknown.

Aims & Methods

The central objective of this study was to understand the molecular mechanisms underlying the associations between IBD and obesity related metabolic diseases. To address this research question, we used multiple mouse models of colitis (dextran sodium sulfate or DSS), DSS and Azoxymethane induced colitis associated colon cancer and Helicobacter hepaticus infection induced colitis in Il-10-/- mice) and high fat diet (HFD) and genetic models of obesity and obesity associated metabolic diseases. In addition, for mechanistic studies, we used chimeric mice generated through bone marrow transplantation as well as conditional knockout mouse models. Lastly, we employed CRISPR/Cas9 edited cells in vitro to understand the molecular mechanism.

Results

Employing multiple murine models of colitis, colitis-associated colon cancer (CAC) and obesity associated metabolic diseases, we have identified DUPD1, a phosphatase of unknown function, that links IBD with metabolic diseases. Specifically, Dupd1^-/-mice are protected from dextran sodium sulfate (DSS) and Helicobacter hepaticus induced colitis, and DSS/azoxymethane (AOM) induced CAC. Dupd1^-/- mice also exhibited protection against high fat diet (HFD) induced obesity and fatty liver disease and glucose intolerance. DUPD1 is highly expressed in the skeletal muscle. Indeed, using skeletal muscle specific conditional DUPD1 knockout mice (Dupd1^fl/flMyf6^Cre), we show that DUPD1 exerts its colitogenic effects from the skeletal muscle through modulation of autophagy, a pathway whose dysfunction is known to play a role in IBD. Importantly, a dual specificity phosphatase inhibitor (NSC-663284) inhibited DUPD1 enzyme activity and reduced DSS-induced colitis in wild type mice but not in Dupd1^-/-mice.

Conclusion

Our study identifies Dupd1 as a central gene that links IBD and obesity-associated metabolic diseases and suggests that it is a new therapeutic target in IBD, and obesity associated metabolic diseases.

Disclosure

Nothing to declare.