Clinical Case Summary

Up to 5% of patients with newly diagnosed Celiac disease, have negative serology. Although seronegative celiac, is the most common cause for villous atrophy, there are other differential diagnoses (D.D) that should be ruled out when we find villous blunting without positive serology for Celiac disease. The etiologies are usually divided to 5 categories: immune-mediated, infectious, iatrogenic, inflammatory and infiltrative.
We hereby report a case of 39 years old male, with end-stage renal failure and pancreatic insufficiency. He was treated with peritoneal dialysis and was candidate for combined kidney-pancreas transplantation. Hyperphosphatemia is a common complication in patients with end-stage renal disease. In order to reduce his serum phosphate levels, he was treated with high dose of Lanthanum Carbonate, one of the most effective and safe noncalcium-based phosphate binders.
During weight loss investigation, he underwent gastroscopy that demonstrated duodenal denudated mucosa with villous blunting (1). Biopsy showed complete villous atrophy and accumulation of foreign material in mucosal histiocytes (2). Von Kossa staining, that was performed, emphasized the depositions of the foreign material that has been identified as Lanthanum (3). Consequently, the treatment with Lanthanum has been stopped and replaced by another phosphate binder.
This case illustrates a rare differential diagnosis of villous atrophy typical for end-stage renal disease patients, that can be categorized as iatrogenic and infiltrative etiology for villous atrophy.
Since the long-term consequences of lanthanum deposition in tissue are unknown, this case also emphasizes the need for multidisciplinary approach for treating dialysis patients, in order to understand which phosphate binder has been given.
Points to discuss:

1. D.D of villous atrophy
2. Seronegative celiac – definition & diagnosis
3. The impact of Lanthanum deposits in human body tissues
4. The need for cooperation of multi-disciplinary team

References

1. Endoscopic picture of duodenal villous atrophy
2. H&E staining that demonstrates complete duodenal atrophy with foreign material in the mucosal histiocytes
3. Von Kossa staining emphasizes the deposits of the foreign material

Disclosure

No conflict of interest to declare

Introduction

Colorectal cancer (CRC) and other bowel diseases is a significant health concern globally. In several countries, the fecal immunochemical test (FIT) is a cornerstone in CRC screening for early detection of cancer in asymptomatic individuals. Moreover, the utility of FIT extends beyond this, as it is increasingly recommended for evaluating symptomatic patients as part of the clinical pathway to render possible or rule out serious bowel pathology. Therefore, we aimed to quantify the findings of serious bowel conditions following a non-screening FIT test in the Danish population.

Aims & Methods

This study investigated use of FIT beyond the national CRC screening program in Denmark. We aimed (1) to assess utilization patterns of FIT in contexts other than screening and (2) to examine ensuing diagnoses. Our goal was to quantify the findings of CRC and other bowel diseases in symptomatic patients, thereby assessing its broader potential.
This cohort study was conducted within the Danish universal public healthcare system, delivered by five administrative regions. National CRC screening using FIT was initiated in 2014, but utilization of FIT for symptomatic patients varies between regions. The cut-off for a positive test is ≥10 µg haemoglobin/g faeces for symptomatic populations.
The study used data from the Danish Civil Registration System, the Danish National Patient Registry covering all Danish hospitals, and the Clinical Laboratory Information Register. The cohort included all patients who underwent FIT between 2014 and 2021 outside the Danish CRC screening program.
We employed descriptive statistics to examine FIT administration and demographic distributions across the Danish regions, as well as fecal haemoglobin levels among tested individuals. In addition, we estimated the cumulative incidence of CRC and inflammatory bowel disease (IBD) diagnoses following FIT, considering death as a competing risk and evaluated the proportion of diagnoses for CRC and IBD during the year following FIT.

Results

We identified 19,787 individuals who underwent FIT outside the national CRC screening program in 2014 to 2021. Of these, 4,283 (22%) individuals had a positive FIT result. Among tested individuals, 10,807 (55%) were female. Median age at testing was 64 years. Use of FIT varied across the regions, with 36% of the study cohort being from the Central Denmark Region, and 1.6% being from the Region of Southern Denmark.
Positive FIT cases had a shorter median time to CRC diagnosis (28 days) and any diagnosis (36 days) compared to negative FIT cases (711 and 58 days, respectively). Within one year of the FIT, 370 (1.9%) individuals were diagnosed with CRC, with higher occurrence for FIT positive individuals (7.9%) than for FIT negative individuals (0.2%) (risk difference: 7.7 percentage points [95% CI: -3.2, 11.1]).
Among individuals with a positive FIT result, 83 (1.9%) were diagnosed with IBD within one year, compared to 51 (0.3%) individuals with a negative FIT (risk difference: 1.6 percentage points [95% CI: -5.8, 7.3]).

Conclusion

We found that FIT used outside the national CRC screening program had over 20% positivity. A positive test indicated higher risk of CRC and IBD. Differences in diagnoses are expected due to varied follow-up procedures after positive and negative FIT results. A negative test, while not definitive, suggests a potential to rule out disease and could reduce unnecessary investigations when assessing symptomatic patients.

Introduction

Multiple treatment choices are available for patients with either Ulcerative Colitis (UC) or Crohn’s Disease (CD) requiring a first biologic therapy, but there is very limited data on comparative efficacy of different agents. Outcomes from robust, large-scale cohort studies can help to inform therapeutic decisions.

Aims & Methods

To compare the efficacy of first line biologic therapies [infliximab (IFX), adalimumab (ADA), golimumab (GLM), vedolizumab (VDZ)] in biologic-naïve patients with UC and CD and enrolled in the UK Inflammatory Bowel Disease (IBD) BioResource. Patients receiving first-line tofacitinib and ustekinumab were excluded from the analysis due to low numbers. Demographic, disease, treatment and outcome data were retrieved. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach accounting for baseline patient or disease related clinical characteristics. Balancing success was assessed with standardized mean differences (SMDs). Effectiveness of treatment was based on persistence free of treatment discontinuation or treatment failure. Failure was defined as occurring if any of the following occurred: (a) clinician-recorded treatment failure (b)start of treatment with a different biologic drug (c)occurrence of resectional or defunctioning bowel surgery. We compared Kaplan Meier curves for treatment failure-free survival after IPTW and used a log rank test for differences between the groups.Cox proportionate hazard ratios (HR)were used for comparisons between treatments.

Results

In total, 12747 patients were included in the analysis (UC=3967, CD=8780). Over a four-year follow up period, treatment survival free of treatment failure or treatment escalation was significantly different between different treatment groups both in UC and CD (log rank p=0.007 and p=0.011 respectively). For UC, we found that VDZ was superior to all anti-TNF agents [vs GLM HR 3.4 (95% CIs 2.2-5.2), vs ADA HR 3.1 (95% CIs 2.1-4.5), vs IFX HR 1.9 (95% CIs 1.3-2.8), all p values <0.001]. When compared between anti-TNF agents IFX was superior to both ADA and GLM [vs ADA HR 1.6 (95% CIs 1.4-1.8), vs GLM HR 1.7 (95% CIs 1.3-2.2)] while no significant difference was detected when ADA and GLM were compared. For CD, IPTW did not achieve optimal balancing for baseline differences in the presence of perianal disease. Restricting analysis to the subgroup with the absence of perianal disease, we did not observe a significant difference in treatment outcomes.

Conclusion

Our study showed superiority of VDZ over anti-TNF agents in biologic naïve patients with UC. This is in accordance with, and extends the findings of, a prior head-to-head trial in UC comparing VDZ and ADA¹. In patients with luminal CD, no difference was detected between VDZ and anti-TNF agents. Our data offer guidance to physicians and patients as to relative drug efficacy for first line therapies in IBD.

References

1. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med. 2019;381(13):1215-1226. doi:10.1056/NEJMoa1905725

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