Introduction

Liver cirrhosis has been considered historically a hypocoagulant disease. However, currently its association with hypercoagulable states, mainly when liver function is impaired, is well established. The presence of a procoagulant phenotype has been suggested for development of spleno-porto-mesenteric axis thrombosis; however, there are no standardized data and no definitive recommendations have been reported in clinical guidelines regarding the screening of mutations related to thrombophilia in these patients.

Aims & Methods

The primary outcome of our study is to analyse the prevalence of inherited mutations associated with thrombophilia in patients with liver cirrhosis and non-tumor splenic portal axis thrombosis in our center. We analyze demographics, clinical features, and disease characteristics.
We retrospectively included all patients with liver cirrhosis and non-tumoral thrombosis of the spleno-porto-mesenteric axis who underwent a thrombophilia study between January 2015- September 2022 in our center. As a thrombophilia study, factor V Leyden mutation, 20210A mutation of the prothrombin gene, proteins C and S, antithrombin, plasmatic homocysteine, and antiphospholipid antibodies were analysed. Data were analysed with SPPS (version 27).

Results

A total of 75 cases were enrolled (61.33 % male; median age: 64.8 ± 12.5 years). At the time of thrombosis patients belonged to Child-Pugh classes A: 64 % (n = 48); B: 29.3 % (n = 22) and C: 6.6 % (n = 5). Etiologies of cirrhosis included: Chronic HCV infection 36 % (n = 27), followed by alcohol-related liver disease 34.6 % (n = 26), indeterminate 9.33 % (n = 7) and MAFLD 6.6 % (n = 5). Most common sites of thrombosis were the portal vein 58.6 % (n = 44), followed by portal branches 10.6 % (n = 10), and 9.3 % (n = 7) in both territories. Regarding the thrombophilia study (Table 1), protein C, S, or antithrombin deficiency were observed in 60 cases (80%). However, mutations related to thrombophilia were detected only in 10.6% of cases (Factor V Leyden: n = 5; 20210A prothrombin mutations: n = 3), lupus anticoagulant in 0.75 % (n = 1) and hyperhomocysteinemia in 4 % (n = 3). Univariate and multivariate analysis did not show statistically significant association between presence of thrombophilia and baseline patient variables such as etiology, Child-Pugh class, MELD score, or thrombosis extent.

Conclusion

Most of the patients in our series presented protein C and S deficiency, probably secondary to their liver disease. However, the prevalence of other mutations related to thrombophilia were very low, like that usually observed in general population, so their screening in cirrhotic patients with thrombosis may be futile in most cases.

Introduction

Dysphagia is a common condition with consequences surpassing the physical dimension and extending to the patient’s psychological, personal, and professional life. However, when referring to non-obstructive esophageal dysphagia (NOD) and motility disorders, data is still scarce.

Aims & Methods

Our study consists in a prospective and multicentric evaluation of the severity of dysphagia and its impact on quality of life, that was measured with the Eckardt, EuroQol-5D (TTO and VAS) and PROMIS GI Disrupted Swallowing (PDS) scores, in patients with NOD and underlying motility disorders. We included 373 individuals (250 with NOD and 123 without dysphagia).

Results

Among patients with NOD, 97 had esophagogastric junction (EGJ) outflow disorders on manometry according to Chicago V4.0, 24 spastic motility disorders, 38 hypomotile disorders and 91 normal motility. Compared with non-dysphagic individuals, dysphagic patients had significantly worse scores of both EuroQol-5D and PDS (p-values <0.001).
Among esophageal motility disorders, Eckardt score was significantly different between groups (p-value <0.001) as determined by ANOVA. Specifically, it was significantly higher in EGJ outflow disorders (mean of 5.2), when compared to spastic motility disorders (mean of 3.3) or dysphagic patients with normal motility (mean of 3.2).
With respect to Patient-reported outcomes, PDS score was statistically different between groups (p-value 0.003), being higher in the EGJ outflow disorders (mean T-score of 64.1) when compared to hypomotiity disorders (mean of 60.2) and dysphagic patients with normal motility (mean of 60.3).
Regarding patient-reported quality of life, there were no differences between groups in terms of EuroQol-5D TTO or VAS score (p-value of 0.156 and 0.368, respectively).

Conclusion

Our findings highlights the impact of NOD on the quality-of-life of patients. Although physician and patient reported symptoms’ severity were worse on EGJ outflow disorders, overall quality of life seems equally affected among all esophageal motility profiles.

Introduction

Enteropathy Associated T Cell Lymphoma (EATL) is a rare and highly aggressive T-cell non-Hodgkin’s lymphoma (NHL)¹ that is strongly associated with refractory coeliac disease (RCD), particularly type 2 RCD ², and possibly inflammatory bowel disease (IBD). The incidence and prevalence of both coeliac disease³ and IBD⁴ have been rising around the world for several decades, including in both Englandand Denmark^​. Some of the potential drivers of EATL are the antigen-driven proliferation of intra-villous T-cells from coeliac disease and chronic inflammation in IBD, so it is important to understand if changes in these diseases are altering clinical presentations of EATL and its survival.

Aims & Methods

Our aim was to describe the contemporary incidence and survival of EATL from two European countries on a national scale, given the rising incidence and prevalence of coeliac disease and use of immunosuppression in inflammatory bowel disease, to give further insights into epidemiology of this rare and often fatal malignancy.
People with EATL were identified from national cancer registries from 2013-2019 in England and 2004-2020 in Denmark. Within each country we used direct standardisation to estimate incidence, Poisson regression to compare incidence between groups and Cox regression to assess overall survival.

Results

172 and 39 patients were identified in England (E) and Denmark (DK) respectively with a mean age at diagnosis of 66 and 68 years. Approximately half of all cases had coeliac disease (E 52%, DK 41%), and ~7% (E 6%, DK 8%) had inflammatory bowel disease (Table). The overall age-standardised incidence rate was (E) 0.48 (95% CI 0.41-0.56) and (DK) 0.44 (95% CI 0.30-0.58) per million population per year. In both countries incidence was higher in older age groups. The 5-year overall survival was 10% (95% CI: 6%-18%) in England and 20% (95% CI: 9%-33%) in Denmark. Those with coeliac disease fared better than those without: (adjusted Hazard Ratio E 0.65 (95% CI 0.45-0.93), DK 0.57 (95% CI 0.26-1.27)).

Table: Characteristics of people with EATL in England (2013-2019) and Denmark (2004-2020)

Conclusion

This analysis of two nationwide cancer registries is the largest population-based study to date to provide contemporary and comprehensive epidemiologic estimates of all ICD-O-3 coded EATL. It shows that a higher incidence is associated with older age, male sex (in England) and that half of cases also have coeliac disease. Our finding of the high proportion of people with inflammatory bowel disease compared to the background prevalence in both countries requires further investigation, as reasons for this are unclear, but it could be related to chronic inflammation or immunosuppression. Overall survival is poor and gets worse in older age groups but is better in those with coeliac disease, following surgical resection and those able to tolerate intensive therapies.

References

1. Ferreri AJ, Zinzani PL, Govi S, et al. Enteropathy-associated T-cell lymphoma. Crit Rev Oncol Hematol 2011;79:84-90.
2. Pelizzaro F, Marsilio I, Fassan M, et al. The Risk of Malignancies in Celiac Disease-A Literature Review. Cancers (Basel) 2021;13.
3. King JA, Jeong J, Underwood FE, et al. Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis. Am J Gastroenterol 2020;115:507-525.
4. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017;390:2769-2778.

Introduction

Chronic fatigue is a debilitating symptom and has major impacts on the quality of life of patients with chronic inflammatory conditions. In IBD, an estimated 50% of patients suffer from persistent fatigue despite successful treatment of intestinal inflammation. During active disease flares, this number jumps to 80% (Borren et al. 2018). Tryptophan metabolites are not only associated with disease activity in UC and CD, but also with chronic fatigue (Kavyani et al. 2022). Thus, our aims are (1) to characterize the relationship between fatigue and tryptophan derivatives and (2) to understand the metabolic dynamics arising when fatigue symptoms improve following therapeutic intervention.

Aims & Methods

In a prospective open label cohort of patients with moderate-to-severe Crohn’s disease (CD, n = 71) and ulcerative colitis (UC, n = 94) assigned to biologics therapy or JAK inhibitors, fatigue was assessed by the fatigue subscale of the Functional Assessment of the Chronic Illness Therapy – Fatigue (FACIT-F) questionnaire at therapy induction and 2 and 14 weeks thereafter. A FACIT-F score of <30.1 was considered severe fatigue while a score of >40 was considered no relevant fatigue. Clinical response at week 14 was defined as Crohn’s Disease Activity Index (CDAI) <150 and reduction of Partial Mayo Clinical Score (PMCS) >50% vs. baseline, respectively. We used targeted mass spectrometry to quantify the levels of 13 tryptophan derivatives and neopterin in a subset of patient serum in the weeks following therapy induction (at 0, 2, and 14 weeks, n = 120 individuals).

Results

Half of the recruited patients had severe fatigue at baseline (50.3%). Of the 120 patients who reached week 14 and had FACIT-F scores available, severe fatigue was experienced by 45.9% of the patients who did not respond to therapy and the rate was reduced to 13.2% in therapy responders. We found 8 metabolites positively associated with FACIT-F: tryptophan, kynurenic acid, kynurenine, picolinic acid, xanthurenic acid, serotonin, indole-3-proprionic acid, and quinaldic acid, while neopterin was negatively associated (FDR < 0.05). Four of these metabolites changed dynamically as a function of the extent of fatigue improvement: tryptophan, kynurenine, xanthurenic acid, and serotonin (FDR < 0.05). In all cases, the rate of change of these metabolites increased as a function of fatigue improvement.

Conclusion

Fatigue is linked to a diverse array of tryptophan metabolites. Notably, all of the significantly associated tryptophan derivatives were positively associated with FACIT-F, meaning that as fatigue symptoms improve, tryptophan metabolite levels increase. Many of these metabolites have previously been linked to symptom severity in IBD: for example, tryptophan, kynurenic acid and xanthurenic acid all tend to increase with symptom alleviation (Nikolaus et al. 2017, Michaudel et al. 2022). While the kynurenine-to-tryptophan ratio is elevated in active IBD (Nikolaus et al. 2017), this ratio did not convey a specific, fatigue-related signature. Considering that some patients continue to suffer from persistent fatigue even during disease quiescence, further work is needed to disentangle the impact of tryptophan metabolism on therapy response from its role on fatigue improvement.

Disclosure

F. Tran receives scientific funding from Sanofi, received consulting fee's from LEK Consulting and speaker's fees from Lilly, Janssen, Falk, Abbvie, Celltrion, onkowissen.de, CED Service GmbH. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk.

Introduction

Esophageal dysphagia is a common complaint in daily clinical practice. After excluding structural and motility disorders, it may be related to functional disorders, which are challenging to diagnose and manage, leading to high health care utilization and both patient and physician dissatisfaction.

Aims & Methods

This is a prospective multicentric 6-months follow-up study to characterize dysphagic patients with normal esophageal motility, in terms of epidemiology and clinical aspects, focusing on patient-reported outcome measures, and evaluate their evolution at 6-months.

Results

From 2021-2024, 91 patients were recruited, 78.0% female, with a median age of 65 years [22-88]. Of these, 27.5% (n = 25) suffered from rheumatologic or endocrinologic disorders, and 56.0% were previously exposed to medical therapies.
Dysphagic symptoms had a median duration of 3 years [1-31], with a median Eckardt of 3 [0-9], PROMIS GI Disrupted Swallowing (PDS) of 60.4 [40.3-84.1], EuroQol-5D TTO of 0.592 [-0.055-1] and VAS of 70 [0-100].
Compared to non-dysphagic participants (n=123), these patients had significantly worse Eckardt, EuroQol-5D and PDS scores (p-values <0.001).
Compared to esophageal motility disorders (Chicago V4.0), the Eckardt and PDS scores in this group were significantly lower when compared to EGJ outflow disorders (p-value <0.001 and 0.003), without differences regarding EuroQol-5D.
Regarding gastroesophageal reflux, 24 (26.4%) patients had a positive GERD-Q questionnaire and 3 had an objective GERD diagnosis. Even though, compared to motility disorders, this score was significantly lower in this group when compared to EGJ outflow disorders (p-value 0.001).
Medical treatments (PPI, amitriptyline) were optimized in 6 patients (6.6%), without any differences in Eckardt or EuroQol-5D scores at 6-months. However, at 6-months, the PDS improved in untreated patients (p-value <0.001).

Conclusion

Non-obstructive dysphagia with normal esophageal motility has a negative impact on quality of life. However, symptoms tend to have a favorable course independently of treatment, therefore mandating a holistic management.

Introduction

Radiation therapy is widely used in the treatment of carcinoma in the abdomen and pelvic cavity, but as a side effect, acute and chronic damage to the gastrointestinal tract may occur. It is well known that the rectum is more prone to radiation damage since it is fixed in the pelvis. Acute symptoms of radiation enteritis are mainly associated with inflammation of the intestinal mucosa and loss of normal mucosa, but changes in gastrointestinal motility due to exposure to high-concentration radiation may also be a cause. Previous studies are demonstrating that patients who received radiation therapy had increased bowel movements, symptoms of urgency, and decreased rectal compliance. But there are only limited studies investigated the pattern of changes in the motility of human rectal smooth muscle following irradiation.

Aims & Methods

This study was conducted to investigate changes in motility and their mechanisms after irradiation in human rectum.
Human rectal tissues were obtained immediately in the operating room from patients undergoing colorectal resection. After removing the mucosal layer of rectum, muscle layer was cut in strips of 5-6 mm in length and 2-3 mm in width. The muscle strips were mounted to an isometric force transducer (Biopac Systems, Inc., Goleta, CA, USA) and suspended in 10 ml organ bath containing aerated (97% O₂ and 3% CO₂) and warmed (36.5 ± 0.5°C) KRB solution. The area under the curve (AUC) for 5 min and tone of spontaneous contractions were analyzed to compared the responses to KCl, ACh (acethylcholine), SNP (sodium nitroprusside), a nitric oxide donor, and ATP (adenosine triphosphate), a purinergic receptor agonist. The mechanical responses were recorded and digitized using Acknowledge software (Biopac Systems, Inc., Goleta, CA, USA). Data were analyzed offline using Clampfit (version 10.2. Molecular devices, San Jose, CA, USA). qPCR was performed for expression of VChAT, NOS1 and PDGFRα to quantify cells mediating cholinergic, nitrergic and purinergic neurotransmission.

Results

KCl and ACh increased the tonic contraction and area under the curve (AUC) in a concentration-dependent manner in both normal and irradiated rectum. The difference in contractile pattern between the two groups was not statistically significant. SNP and ATP decreased AUC and reduced tonic contractions in a concentration-dependent manner in both normal and irradiated rectum. The response to SNP between the two groups was not statistically significant. However, the response to ATP reduced significantly in irradiated rectum compared to normal rectum. In addition, expression of VAChT and NOS1 which are related with cholinergic and nitrergic neurotransmission was not different in both normal and irradiated rectum, however, PDGFRα expression which is related with purinergic neurotransmission was significantly decreased in irradiated rectum compared to normal rectum.

Conclusion

In this study, we analyzed contractile changes in irradiated rectum using neurotransmitters. There were no differences in contractile responses to KCl and ACh and in relaxation response to SNP, however, the relaxation response to ATP was significantly reduced in irradiated rectum. Cholinergic and nitrergic neurotransmission were not changed, however, purinergic neurotransmission was decreased in in irradiated rectum.
These results may explain one of the causes by which increased bowel movements, symptoms of urgency, and decreased rectal compliance in irradiated patients.

Introduction

Treatment of non-obstructive esophageal dysphagia (NOD) should consider not only the primary condition, but also its impact on patients’ daily function, their perception and surgical risk. Between surgical, endoscopic, and medical therapies, there is a wide range of choices, most without well-established indications or outcomes.

Aims & Methods

This is an ongoing prospective multicentric study to evaluate the real-life approach to NOD in 7 centers, by comparing the efficacy of different treatments [per-oral endoscopic myotomy (POEM), botulinic toxin (BT), pneumatic dilation (PD), optimization of proton-pump inhibitors (PPI) and expectant], through the Eckardt, EuroQol-5D (TTO and VAS) and PROMIS GI Disrupted Swallowing (PDS) scores.

Results

According to Chicago V4, it included 97 esophagogastric junction (EGJ) outflow disorders, 24 spastic motility disorders, 38 hypomotile disorders and 91 dysphagia with normal manometry. Fifty-seven (22.8%) patients were submitted to therapy.
Forty-three (44.3%) patients with EGJ outflow disorders were treated (31 POEM, 5 BT, 2 PD, 1 surgical and 4 medical). In contrast to untreated, treated patients showed better differences in Eckardt, PDS and EuroQol-5D VAS scores (p-values <0.005) after 6 months.
PPI was introduced and/or optimized in five (13.2%) patients with hypomotile disorders. There were no differences in Eckardt, EuroQol-5D and PDS at 6-months in treated or untreated patients.
Three (12.5%) patients with spastic motility disorders were treated (2 BT and 1 calcium-channel blocker). Both treated and untreated showed no differences in Eckardt or EuroQol-5D scores at 6 months.
Regarding dysphagic patients with normal manometry, medical treatments were optimized in 6 patients (6.6%), without any differences in Eckardt and EuroQol-5D scores at 6-months. Interestingly, the PDS showed a better difference at 6 months in untreated patients (p-value <0.001).

Conclusion

Apart from EGD outflow disorders, which have well-established treatment options, real-life approach of NOD is heterogeneous and showed no clear benefit. To improve clinical results, specialized clinics must be created.