Clinical Case Summary

Case: A 72-year-old female. She has been receiving treatment for asthma for 20 years and started using mepolizumab three years ago. Since then, she has had no attacks, and there has been no systemic steroid administration. She presented with fever and fatigue persisting for three days, and liver enzyme elevation and HBs antigen positivity were noted. These were negative in tests done one year prior to admission. Reactivation of hepatitis B virus was suspected, and she was started on entecavir. A liver biopsy showed findings consistent with hepatitis B. Tests for HBV antigens and antibodies were also consistent with reactivation. She developed altered consciousness and coagulopathy the day after admission, leading to a diagnosis of acute liver failure. Plasma exchange, systemic steroid administration, and supportive therapy for hepatic encephalopathy were conducted. Her overall status improved, and she was discharged on the 18th day of admission. She is currently being monitored as an outpatient while continuing entecavir.
Discussion: Reactivation of HBV is frequently reported in immunocompromised patients such as those undergoing chemotherapy. Mepolizumab specifically binds to human interleukin-5, reducing eosinophil counts. It is widely used for severe asthma and eosinophilic granulomatosis with polyangiitis. While there have been no previous reports of HBV reactivation associated with the use of mepolizumab, the Japanese College of Rheumatology recommends taking similar precautions as with other immunosuppressive drugs. While it is unlikely that mepolizumab poses a high risk of HBV reactivation due to its mechanism of action, there is a risk of de novo hepatitis B with its use, necessitating regular monitoring of infection status and preventive treatment based on guidelines.
Conclusion: We experienced a case of de novo hepatitis B due to mepolizumab but successfully managed with intensive therapy. We report this case with a literature-based discussion.

References

1. Cheng J, Li J Bin, Sun QL, Li X. Reactivation of hepatitis B virus after steroid treatment in rheumatic diseases. J Rheumatol. 2011;38(1):181–2.
2. Kusumoto S, Tanaka Y, Suzuki R, Watanabe T, Nakata M, Takasaki H, et al. Monitoring of hepatitis b virus (HBV) DNA and risk of HBV reactivation in B-cell lymphoma: A prospective observational study. Clin Infect Dis. 2015;61(5):719–29.
3. Hui CK, Cheung WWW, Zhang HY, Au WY, Yueng YH, Leung AYH, et al. Kinetics and Risk of De Novo Hepatitis B Infection in HBsAg-Negative Patients Undergoing Cytotoxic Chemotherapy. Gastroenterology. 2006;131(1):59–68.
4. Iannitto E, Minardi V, Calvaruso G, Mulè A, Ammatuna E, Trapani RD, et al. Hepatitis B virus reactivation and alemtuzumab therapy. Eur J Haematol. 2005;74(3):254–8.
5. Lau GKK, Liang R, Chiu EKW, Lee CK, Lam SK. Hepatic events after bone marrow transplantation in patients with hepatitis B infection: A case controlled study. Bone Marrow Transplant. 1997;19(8):795–9.

Clinical Case Summary

Case 1: A 38-year-old male with stricturing ileocolic Crohn’s disease on adalimumab underwent a colonoscopy, which revealed active disease (SES-CD: 8) where biopsies were taken. The procedure was uneventful. However, the following day, he developed severe right upper quadrant (RUQ) pain, prompting emergency evaluation. He was afebrile but exhibited RUQ tenderness. Blood tests revealed leukocytosis (21.0×10⁹/L) and elevated CRP (4.26mg/dL). CT scan revealed pericolic fat stranding at the hepatic flexure extending to the gallbladder. Due to diagnostic uncertainty, observation with antibiotics was initiated. Clinical deterioration and worsening inflammatory markers led to an ultrasound, which confirmed an acute cholecystitis. Patient underwent laparoscopic cholecystectomy, revealing gangrenous cholecystitis with perforation. He was discharged on postoperative day 3 with full recovery.
Case 2: A 63-year-old female with a history of stricturing ileocolic Crohn’s disease (ileocecal resection in 2001) and ascending colon adenocarcinoma (right hemicolectomy in 2009) underwent a colonoscopy, which was uneventful. The next day, she developed RUQ pain and vomiting, prompting emergency evaluation. She was febrile with RUQ tenderness. Laboratory results showed leucocytosis (10.6×10⁹/L) and elevated CRP (9.11mg/dL). Ultrasound confirmed acute cholecystitis. She underwent urgent laparoscopic cholecystectomy and was discharged two days later without complications.
Conclusions: We report two cases of acute cholecystitis occurring within 24 hours of colonoscopy. Sixteen similar cases exist in the literature, most presenting within 72 hours¹. Crohn's disease activity does not appear to be a contributing factor, as one patient had no active inflammation. Proposed mechanisms include dehydration, bacterial translocation, trauma and inflammatory response². Finally, given the high frequency of colonoscopy and the prevalence of cholecystitis, a coincidental association cannot be excluded.

References

1. Neubeck KM, Mwagiru D, Boseto EF Acute cholecystitis following elective colonoscopy BMJ Case Reports CP 2023;16:e257166.
2. Shaikh D H, Kumar K, Patel H, et al. (October 10, 2020) Acute Cholecystitis, A Rare Complication Following Routine Colonoscopy: Case Series and Literature Review. Cureus 12(10): e10877.

Introduction

Colorectal cancer (CRC) remains the second most common cause of cancer-related mortality worldwide (1). The introduction of the Danish national CRC screening program in 2014 aimed at reducing mortality rates (2) has marrkedly increased colonoscopies and polypectomies (3,4). A a comprehensive description of the lesions removed has not yet been investigated.

Aims & Methods

Nationwide, cross‑sectional study of all colorectal lesions resected endoscopically in patients ≥18 years between January 2014 and December 2021. Data were obtained from the Danish National Patient Register, Pathology Register and Screening Database. Prevalence of histological sub‑types and predictors of high‑grade dysplasia (HGD) and adenocarcinoma were analyzed with multivariable logistic regression.

Results

Among 663,624 individuals undergoing 1,074,236 colonoscopies or sigmoidoscopies, 194,941 patients (median age 67 years, 58.6% male) had a total of 504,386 lesions removed. Tubular adenomas (TA) accounted for 66.8% of lesions.
The proportion of advanced colorectal polyps—defined as lesions ≥10 mm, adenomas with high-grade dysplasia, or sessile serrated lesions with any dysplasia—declined from 22.7% in 2014 to 10.2% in 2021.
High-grade dysplasia (HGD) was strongly associated with size ≥10 mm (OR 27.1 for 10–19 mm; OR 71.1 for 30–39 mm), and in diminutive lesions (1–5 mm), with tubulovillous or villous histology (OR 6.09).
Adenocarcinoma was identified in 0.65% of lesions and was predominantly left-sided (83.9%), with highest odds observed in the sigmoid colon (OR 6.33) and rectum (OR 6.00), compared to the caecum.
Sex was significantly associated with the risk of adenocarcinoma at the lesion level, but this effect was age-dependent. At age 40, women had significantly higher odds than men (adjusted OR 1.48), but the difference diminished with increasing age, and from age 75 onward, no statistically significant difference between sexes was observed.

Conclusion

Lesion size was the strongest predictor of high-grade dysplasia, outweighing histologic subtype once lesions exceeded 10 mm. At lesion level, the risk of malignancy was higher in younger women than in men of the same age, with the difference progressively diminishing with age. The introduction of the screening programme coincided with a marked reduction in advanced lesions over time. The high predominance of left-sided cancerous lesions highlights the need to optimize the detection of right-sided neoplasia.

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin [Internet]. 2021 May 1 ;71(3):209–49. Available from: https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21660
2. Kanth P, Inadomi JM. Screening and prevention of colorectal cancer. BMJ [Internet]. 2021 Sep 15;374. Available from: https://www-bmj-com.ez.statsbiblioteket.dk/content/374/bmj.n1855
3. Adamsen S, Mosbach KKT, Milliam PB, Hansen OH. Injuries by colonoscopy and sigmoidoscopy requiring laparotomy. Claims to the Patient Insurance Corporation. Ugeskr Laeger. 2007 May 7;169(19):1788–93.
4. Baatrup G. Lokal resektion af tidlige kolorektale cancere - og hvad gør vi så?. Ugeskr Laeger. 2021 Jun 28;183(26).

Introduction

Autism Spectrum Disorder (ASD) is closely associated with gut-brain axis dysfunction[1]. Fecal microbiota transplantation (FMT) may alleviate gastrointestinal and behavioral symptoms in ASD children by remodeling gut microbiota[2], yet the key functional bacterial strains underlying FMT-mediated neurobehavioral regulation remain unidentified.

Aims & Methods

This study aims to systematically evaluate FMT efficacy through a cohort study, combined with metagenomic analysis to investigate the dynamic patterns of microbiota colonization in ASD children. We will thoroughly identify core bacterial strains and analyze the relationship between their colonization patterns and therapeutic outcomes. The children aged 0-18 years meeting the diagnostic criteria for ASD were included in this study. The clinical data of recipients was collected before FMT, alongside questionnaire surveys and fecal sample collection. Pre-FMT assessments were conducted by pediatric psychologists using standardized scales. Donor feces were extracted via standardized protocols, and 100 mL of donor microbiota suspension was administered into the jejunum or ileum via colonoscopy or nasojejunal tube once every other day, total three sessions. Post-FMT fecal samples were collected from recipients at 1, 2, 4, 12, and 24 weeks for metagenomic analysis at species and strain levels. At 12 and 24 weeks post-FMT, the same psychologists reevaluated recipients using assessment scales, while parents completed follow-up questionnaires to document clinical outcomes. Finally, correlation analysis was conducted between laboratory data and clinical outcomes.

Results

A total of age-matched healthy pediatric donors (86 fecal samples) and 52 ASD children (351 fecal samples) were included. Results revealed that 69.2% of ASD children exhibited gastrointestinal (GI) symptoms (e.g., constipation or diarrhea), 58.3% had one or more food protein allergies, and 78.5% experienced sleep disturbances (<8 hours/day). Post-FMT, GI symptoms improved most significantly: 80% of recipients showed at least one grade reduction in Gastrointestinal Symptom Rating Scale (GSRS) scores, while 60% demonstrated improvements in autism-related behavioral traits, including reduced emotional dysregulation/negativity and enhanced sensory responsiveness. Clinical improvements became more pronounced over time. Metagenomic analysis demonstrated a significant increase in gut microbiota diversity and structural remodeling in recipients, with microbial profiles converging toward donor compositions. Correlation analysis identified donor-derived Bacteroidetes and Bacillota phyla as closely associated with clinical improvements.

Conclusion

FMT can significantly and 'long-term' reconstruct the gut microbiota of children with autism, effectively alleviating concurrent symptoms such as gastrointestinal disorders. Successful colonization of Bacteroidetes and Bacillota from donor sources is closely related to clinical improvement.

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.
2.Dossaji Z, Khattak A, Tun KM, Hsu M, Batra K, Hong AS. Efficacy of Fecal Microbiota Transplant on Behavioral and Gastrointestinal Symptoms in Pediatric Autism: A Systematic Review. Microorganisms. 2023 Mar 22;11(3):806.

Introduction

Coeliac disease (CeD) is an autoimmune enteropathy of the small intestine triggered by gluten. Some clinical studies comparing CeD patients to healthy controls have suggested that CeD is a cardiovascular risk factor. In this study, we aimed to investigate the cardiovascular effects of CeD in a humanized CeD mouse model, focusing on vascular inflammation, endothelial dysfunction, and oxidative stress (in relation to intestinal inflammation), which are known triggers for later cardiovascular diseases and their mechanistic causes.

Aims & Methods

NOD-human DQ8 transgenic mice with genetic deletion of the murine MHCII complex (NOD-DQ8 mice), genetically predisposed to CeD, were raised on a zein (corn)-protein-based, gluten-free diet. Gluten sensitization was performed by 3 oral gavages of pepsin-trypsin digested and TG2 deamidated gliadin (500 µg) and cholera toxin (25 µg), concomitant with the feeding of a gluten-containing diet (gliadin group) for 14 days. A control group continued the gluten-free diet during sensitization with zein. An additional group was returned to a gluten-free diet for another 14 days to assess the reversibility of CeD and cardiovascular effects. Small animal transthoracic echocardiography (TTE) as well as non-invasive blood pressure measurements were performed. Vascular function was tested by isometric tension recording. Aortic, cardiac, perivascular adipose (PVAT) and duodenal tissue were used for qRT-PCR, dot blotting, Flow Cytometry or IHC to determine the extent of vascular and intestinal inflammation as well as (nitro-)oxidative stress. Plasma proteomics was performed using Olink.

Results

As in human CeD, gluten-challenged NOD-DQ8 mice developed a duodenal and jejunal infiltration of intraepithelial T-lymphocytes (IELs) and a reduction in the villus/crypt ratio. Tail-cuff measurements showed increased blood pressure in these mice compared to the controls. Endothelium-dependent (ACh) and -independent (NTG) vascular relaxation was impaired, as tested by isometric tension measurements, and transcripts of pro-inflammatory genes (Il6, Infy, Tnfa, Cybb-Nox2, Nos2-iNos) were upregulated in the duodenum and aorta. Flow cytometry revealed increased CD11b+ myeloid cell infiltration into the aortic wall in gluten-challenged NOD-DQ8 mice. Additionally, oxidative stress parameters 3-nitrotyrosine (3-NT) and 4-hydroxy-2-nonenal (4-HNE) were elevated in the heart tissue, as demonstrated by dot-blot analysis. However, cardiac function remained unimpaired, as assessed by TTE. To investigate the inflammatory gut-vascular connection, plasma proteomics tests (Olink) were performed, which showed increased concentrations of IL-17A, confirmed by ELISA. The cardiovascular complications were reversible with the return to the gluten-free diet.

Conclusion

In our humanized CeD mouse model, active CeD increases blood pressure and impairs vascular function. We conclude that CeD increases cardiovascular risk through gut inflammation that is transferred to the cardiovascular system, leading to vascular inflammation/oxidative stress and impaired endothelial function. A possible mediator is IL-17A whose role in other autoimmune diseases like psoriasis has already been demonstrated.
With the present study, we demonstrate a mechanistic approach to explain the role of coeliac disease as a cardiovascular risk factor and provide evidence for a gut-to-cardiovascular inflammatory axis.