Introduction

Endoscopy abnormalities of eosinophilic esophagitis (EoE) are currently graded based on the EoE endoscopic reference score (EREFS) ranging 0 to 9. Research has shown that esophageal biopsies are often omitted in Europe in patients reporting dysphagia when the upper endoscopy (EGD) shows no abnormalities [1]. However, a proportion of patients with eosinophilic esophagitis (EoE) may have normal endoscopy (i.e., EREFS=0), making the diagnosis more difficult and increasing the risk of diagnostic delay.

Aims & Methods

We investigated predictors of a diagnosis of EoE when the EGD is unremarkable (i.e., EREFS=0). Consecutive adult patients (≥18 years) with dysphagia who had EREFS=0 at an EGD with six esophageal biopsies were prospectively enrolled. All patients underwent EGD while off any eosinophil-depleting treatment. EoE with EREFS=0 was diagnosed based on the presence of at least 15 eosinophils/high-power field in at least one of six esophageal biopsies. When all six esophageal biopsies showed <15 eosinophils/high-power field, patients were diagnosed with non-EoE dysphagia (NED). Demographics, diagnostic delay (i.e., interval time between symptoms onset and diagnosis), esophageal symptoms, and atopic comorbidities (i.e., allergic rhinitis, asthma, eczema) were collected for all patients. Pearson's Chi-squared test and Fisher's exact test were used for comparisons. Odds ratios (ORs) were calculated to quantify associations between disease states. Significance threshold was set at p<0.05.

Results

Of 133 included patients, 51 (38%) had NED, while 82 (62%) had EoE with EREFS=0. Patients with EoE were more commonly males (67% vs 35%; p<0.001) and younger (37 vs 46 years; p=0.005) compared to patients with NED. Patients with EoE were diagnosed with a significantly longer diagnostic delay than NED (28 vs 4 months; p<0.001). Heartburn, regurgitation, chest pain and dyspepsia had similar prevalence in the two groups. In contrast, patients with EoE had a significantly higher prevalence of atopic comorbidities compared to NED (83% vs 39%; p<0.001).
The presence of rhinitis, diagnostic delay longer than 12 months, any atopic comorbidity, age younger than 37 years, and male sex were associated with an increased risk of EoE with OR of 47.0, 11.6, 7.4, 3.8, and 3.7, respectively (p<0.01 for all).

Conclusion

EoE remains a possible diagnosis in patients reporting dysphagia even when endoscopy is normal. The presence of rhinitis and longer diagnostic delay, the presence of any atopic comorbidity, and younger age are associated with a diagnosis of EoE and are helpful to raise the suspicion of EoE and prompt endoscopists to collect esophageal biopsies.

References

[1] Tourlamain, G., Garcia-Puig, R., Gutiérrez-Junquera, C., Papadopoulou, A., Roma, E., Kalach, N., Oudshoorn, J., Sokollik, C., Karolewska-Bochenek, K., Oliva, S., Strisciuglio, C., Bauraind, O., Auth, M. K., Thomson, M., Otte, S., Rok, O., Dias, J. A., Tzivinikos, C., Urbonas, V., Kostovski, A., … ESPGHAN EGID Working group (2020). Differences in Management of Eosinophilic Esophagitis in Europe: An Assessment of Current Practice. Journal of pediatric gastroenterology and nutrition, 71(1), 83–90. https://doi.org/10.1097/MPG.0000000000002672

Introduction

Splenomegaly can exacerbate liver cirrhosis and portal hypertension. Thus, inhibiting splenomegaly may be a novel treatment for liver cirrhosis. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the transcriptome profiles and precise pathogenesis of cirrhotic splenomegaly remain unknown, and few effective therapies are available. The role and mechanism of cyclooxygenase-2 (COX-2) in cirrhotic splenomegaly remain unclear.

Aims & Methods

Aims: We attempt to identify the transcriptomic profile of cirrhotic spleen, providing comprehensive valuable information for pathogenesis of splenomegaly. And to further validate the protective role of celecoxib on cirrhotic splenomegaly.
Methods: Thirty male Sprague-Dawley rats were randomized into the control group, TAA and TAA+Celecoxib groups. The control group: received intraperitoneal injection of normal saline (1ml, twice a week); the TAA group: received intraperitoneal injection of thioacetamide (TAA, 200 mg/kg, twice a week for 16 weeks); the TAA+celecoxib group: received TAA intraperitoneally and celecoxib via gastric gavage (20 mg/kg/day). Splenic gene profiling was analyzed by high-throughput RNA sequencing. Histological analysis of spleen tissue was evaluated by H&E, Sirius red, Prussian blue staining, and transmission electron microscopy. The splenic mRNA levels of collagen III and α-SMA and splenic contents of Ki-67 and VEGF were quantified.

Results

A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib can ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA+celecoxib vs. TAA. According to GO and KEGG analyses, celecoxib may attenuate cirrhotic splenomegaly by suppressing splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts of celecoxib on splenic immune cell proliferation, inflammation, immune regulation, and extracellular matrix were then validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA.

Conclusion

Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study further validate that COX-2 inhibitors could serve as a novel medical treatment for cirrhotic splenomegaly based on transcriptomic analysis.

Introduction

Autonomic neuropathy affecting multiple organs is a common and severe complication of diabetes¹. Neuropathy of the enteric nervous system and the regulatory autonomic nerve fibers can affect the entire gastrointestinal tract, causing mild to severe gastrointestinal symptoms². The correlation between gastrointestinal symptoms and underlying pathophysiology is generally weak, so objective assessment is important to guide treatment^3-5. Methods for direct evaluation of enteric neuropathy are not yet available in clinical practice. Hence, gastrointestinal transit times and contractile activity are used as proxies for enteric autonomic dysfunction^6,7. Panenteric gastrointestinal assessment is considered essential, yet suitable methods are generally inaccessible, and diagnosing diabetic gastroenteropathy often causes significant challenges^4,8. It is unknown whether measures of extraintestinal autonomic function can reflect diabetic gastroenteropathy and whether these measures could serve as supplementary diagnostic tools.

Aims & Methods

We aimed to assess 1) whether gastrointestinal symptoms are associated with motility measures and 2) whether gastrointestinal symptoms/motility measures are associated with extraintestinal autonomic markers. We included 81 persons with type 1 or type 2 diabetes (65% female, mean age 54) with gastrointestinal symptoms and either symptoms or signs of autonomic neuropathy. The Gastroparesis Cardinal Symptom Index (GCSI) and the Gastrointestinal Symptom Rating Scale (GSRS) were used to assess gastrointestinal symptoms. The wireless motility capsule assessed panenteric transit times and motility indices. Cardiovascular reflex tests performed with the VAGUS device and the cardiac vagal tone assessed with the eMotion Faros device estimated cardiovascular autonomic neuropathy, while the SUDOSCAN evaluated sudomotor function.

Results

Proximal gastrointestinal symptoms were positively associated with the gastric motility index (GCSI: 1.18 (1.04 - 1.35), p=0.01; GSRS: 1.15 (1.03 - 1.29), p=0.02; median ratio (95%CI)), while only satiety reflected gastric emptying time (1.24 (1.03 - 1.49), p=0.02). Diarrhea was associated with decreased small bowel transit time (0.93 (0.89 - 0.98), p=0.005), while constipation was associated with prolonged colonic transit time (1.16 (1.03 - 1.31), p=0.02). Gastrointestinal symptoms increased with the degree of abnormal cardiovascular reflex tests (GCSI: 0.67 (0.16 - 1.19), p=0.03; GSRS: 0.87 (0.30 - 1.45), p=0.01; mean difference (95%CI)) but not with motility measures. Cardiac vagal tone and sudomotor function were not associated with gastrointestinal markers.

Conclusion

Gastrointestinal and extraintestinal autonomic measures were not associated. However, proximal gastrointestinal symptoms were associated with the gastric motility index and cardiovascular reflex tests. Hence, the latter may contribute to evaluating whether proximal gastrointestinal symptoms are autonomically derived.

References

1. Verrotti A, Prezioso G, Scattoni R, Chiarelli F. Autonomic neuropathy in diabetes mellitus. Front Endocrinol (Lausanne). 2014;5:205.
2. Azpiroz F, Malagelada C. Diabetic neuropathy in the gut: pathogenesis and diagnosis. Diabetologia. 2016;59(3):404-408.
3. Arora Z, Parungao JM, Lopez R, Heinlein C, Santisi J, Birgisson S. Clinical utility of wireless motility capsule in patients with suspected multiregional gastrointestinal dysmotility. Dig Dis Sci. 2015;60(5):1350-1357.
4. Kuo B, Maneerattanaporn M, Lee AA, et al. Generalized transit delay on wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. Dig Dis Sci. 2011;56(10):2928-2938.
5. Rouphael C, Arora Z, Thota PN, et al. Role of wireless motility capsule in the assessment and management of gastrointestinal dysmotility in patients with diabetes mellitus. Neurogastroenterol Motil. 2017;29(9).
6. Kempler P, Amarenco G, Freeman R, et al. Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes. Diabetes Metab Res Rev. 2011;27(7):665-677.
7. Camilleri M, Chedid V, Ford AC, et al. Gastroparesis. Nat Rev Dis Primers. 2018;4(1):41.
8. Bertoli D, Mark EB, Liao D, et al. MRI-Based Quantification of Pan-Alimentary Function and Motility in Subjects with Diabetes and Gastrointestinal Symptoms. J Clin Med. 2023;12(18).