Clinical Case Summary

A 27-year-old woman is admitted to a tertiary hospital for a sudden painful wound on the inner side of her upper arm. The patient stated that she had been diagnosed with ulcerative colitis 6 years ago and had been treated with prednisone and mesalazine, but was currently in remission and discontinued treatment. She was treated twice in the surgical ward for similar ulcers 2-3 years ago. Physical examination revealed a redness of ~10x6 cm in the lower third of the left upper arm and a necrotic area of 3 cm in the middle of the upper arm which was very painful to palpate. The patient was hospitalized for suspected extraintestinal signs of ulcerative colitis, but colonoscopy revealed no changes. The wound was treated with incision, lavage, necrectomy and a/b therapy according to the culture results. During the course of treatment, the patient developed a new skin lesion on the right hip and an unexpected decrease in prothrombin from 70% to 6%, which normalized after vitamin K injections. A wound biopsy revealed necrotic-inflammatory lesions, differentiating between autoimmune vasculitis and possible chemical damage. Suspecting a factitious disorder (Munchausen syndrome) the patient's rucksack was searched and syringes together with a small vial of liquid (subsequently identified as formalin) were found. Furthermore, it was revealed that patient's son was treated for 10 months in the other hospital due to deep necrotic wounds that are difficult to heal, immunodeficiency of unknown origin, repeated disruptions in the coagulation system (prothrombin 3%) and dead at age 11 month from secondary sepsis 2 years ago.
The hospital appealed to the prosecutor's office, a forensic psychiatric expert found the patient guilty, and the court sentenced her to 16 years' imprisonment for killing her son.

Introduction

Total retocolectomy with ileal pouch anal anastomosis (IPAA) is the surgical procedure of choice for patients with ulcerative colitis (UC) refractory to clinical treatment and familial adenomatous polyposis (FAP) with many polyps in the rectum. Primary ileitis of the ileal pouch (IP) is one of the most common complications in UC, being rare in FAP. Previous studies have identified an increase in pro-inflammatory cytokines, as well as alterations in the apoptosis and macroautophagy pathways markers in the IP mucosa of UC patients, compared to those with FAP and normal distal ileum (controls). Since autophagy and apoptosis can be modulated by endoplasmic reticulum (ER) stress, we investigated this pathway in IP of UC compared to PAF and controls.

Aims & Methods

The aim was to evaluate the modulation of ER stress in the IP mucosa of UC and FAP patients who underwent IPAA, compared to controls. Thirty-two patients were included, ten in the UC group, twelve in FAP group and ten in the control group. Patients who had undergone ileostomy closure for less than one year and had clinical, histological, or endoscopic evidence of pouchitis were excluded. The patients underwent routine colonoscopy, and biopsies were performed from the IP. For the control group, biopsies were taken from the normal distal ileum. The local Ethics Committee approved the study. The biopsies were processed for RNA extraction and subsequent gene expression analysis using the quantitative PCR (qPCR) technique. The following transcripts were investigated: IRE1 (ERN), PERK (EIF2AK3), ATF6, GRP78 (HSPA5), GRP94 (HSP90B1), ATF3, STC2, DDIT3, DNAJC3, and CALR. Nonparametric tests were used for statistical analysis, with a significance level of p<0.05.

Results

The pouchitis disease activity index (PDAI) was applied to verify the absence of pouchitis, with all patients scoring lower than 7. There was no increase in the transcriptional level of the main ER stress pathway markers (ERE1, PERK, and ATF6) in the IP without pouchitis. However, there was a significantly lower expression of DDIT3 in the UC and FAP groups compared to the control (p≤0.05), which may suggest a deficiency in counterbalance the ER stress activation. On the other hand, concerning the UPR pathway markers, the levels of CALR and HSP90B1 were significantly higher in the IP of UC compared to the respective IP afferent loop (p≤0.05), supporting potential activation of the ER stress in the IP in the UC group. Additionally, the transcriptional level of ATF3 was significantly higher in the PAF group compared to the control (p≤0.05), which may indicate a counter-regulatory mechanism in response to tissue damage, which was not verified in the UC group.

Conclusion

Our findings demonstrated that markers of the unfolded protein response (UPR) signaling pathway, which is activated in response to ER stress, are modulated in the IP mucosa of UC patients, even in the absence of pouchitis. These results may explain the propensity to IP inflammation in UC patients. They may guide the identification of additional molecular pathways contributing to inflammation of the IP and the search for new therapeutic targets.

References

1. Negreiros LMV, Pascoal LB, Genaro LM, et al. Pouchitis: insight into the pathogenesis and clinical aspects. Am J Transl Res. 2022 Jul 15;14(7):4406-4425.
2. Rodrigues BL, Dotti I, Pascoal LB, et al. Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation. Mediators Inflamm. 2022 Feb 9;2022:6049500.
3. Paiva NM, Pascoal LB, Negreiros LMV, et al. Ileal pouch of ulcerative colitis and familial adenomatous polyposis patients exhibit modulation of autophagy markers. Sci Rep. 2018 Feb 8;8(1):2619.
4. Qiao D, Zhang Z, Zhang Y, Chen Q, Chen Y, Tang Y, et al. Regulation of Endoplasmic Reticulum Stress-Autophagy: A Potential Therapeutic Target for Ulcerative Colitis. Front Pharmacol. 2021;Volume 12-2021.

Clinical Case Summary

Background: Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome in which the symptomatology of intestinal obstruction occurs without any mechanical cause. This syndrome may reveal or complicate celiac disease during follow-up.
Cases presentation: We report two cases of 40 and 24-year-old women. The first is followed since the age of 8 for celiac disease on a poorly followed gluten-free diet and consulted for repeated pseudo-occlusive syndromes. the second was admitted to the surgery department for a recurrent occlusive syndrome which resolves after gastric aspiration, then referred to our service for exploration of chronic diarrhea. For both, no mechanical obstruction was found. Ionic disorders and lymphoma were also ruled out. The diagnostic of CIPO was retained. The intestinal mucosal biopsy was characteristic of celiac disease. The evolution was favorable under a gluten-free diet. Symptoms of CIPO never recurred.
Conclusion: Our observations highlight that CIPO may be a rare and severe complication of celiac disease, which should always be suspected since the gluten-free diet can improve symptoms and prevent recurrences.