Introduction

Bile acid malabsorption (BAM) arises from dysregulation of enterohepatic bile acid recycling and production, often manifesting as chronic, debilitating diarrhoea. Current first-line treatment involves bile acid sequestrants (eg.cholestyramine, colesevelam). However, response rates and tolerance to these treatments have been inconsistent.

Aims & Methods

This study aims to evaluate the management outcomes in our patients diagnosed with BAM over a five-year period. A retrospective analysis was conducted on 353 patients who underwent SeHCAT testing for suspected BAM from January 2019 for a five-year period. Clinical data, including treatment regimens, response and ancillary investigations, were extracted from medical records and analysed.

Results

Of the 353 patients reviewed, 175 (49.57%) were diagnosed with BAM, with over 90% presenting with chronic diarrhoea. Of these, using NICE guidelines, 47(26.86%) had mild, 63(36%) had moderate and 65(37.14%) had severe BAM. The main referrals for SeHCAT came from Gastroenterologists (76.44%); the remaining 41 patients were largely picked up by Colorectal surgeons with an interest in lower GI physiology, other referring specialties included other colorectal surgeons, general medicine, care of the elderly, respiratory medicine and even urology. Among these, 105 patients were prescribed cholestyramine; however, 47 of these were excluded from further analysis due to lack of follow-up data. Of the 58 evaluable patients, 55% demonstrated symptom improvement, while many experienced side effects such as headaches and abdominal discomfort, leading to poor adherence. For patient’s intolerant to cholestyramine, 34 were transitioned to colesevelam, with 50% reporting symptom relief. Among responders, 47% showed significant symptom control. Notably, 60% of all BAM-diagnosed patients were not followed up by specialty care and were discharged prematurely. Interestingly, co-prescribing antidiarrhoeals with bile acid sequestrants yielded a 100% response rate with no adverse effects reported.

Conclusion

Our findings highlight critical gaps in the management of BAM. Poor compliance with cholestyramine, primarily due to side effects, underscores the importance of individualized treatment plans and patient education. Furthermore, inadequate follow-up care likely contributed to suboptimal treatment outcomes. Severe BAM, as indicated by SeHCAT scores, correlated with poorer treatment responses, suggesting the need for alternative therapeutic strategies. Co-prescribing antidiarrhoeals alongside sequestrants showed promising efficacy and tolerability, potentially reducing the need for higher doses of sequestrants and their associated side effects. These findings call for improved follow-up protocols, patient-centered approaches to medication management, and further exploration of combination therapies to enhance outcomes in BAM management.

References

1. Orekoya O, McLaughlin J, Leitao E, Johns W, Lal S, Paine. Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy. P.Clin Med (Lond). 2015 Jun;15(3):252-7. doi: 10.7861/clinmedicine.15-3-252.
2. Kurien M, Thurgar E, Davies A, Akehurst R, Andreyev. Challenging current views on bile acid diarrhoea and malabsorption. J.Frontline Gastroenterol. 2018 Apr;9(2):92-97. doi: 10.1136/flgastro-2017-100808. Epub 2017 Jun 29.
3. NICE guidelines: SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea: Diagnostics guidance; Reference number:DG44; Published: 17 November 2021

Introduction

Crohn’s Disease (CD), a subtype of Inflammatory Bowel Disease (IBD), is believed to arise from complex interactions between gut microbes, environment, and genetics. A significant proportion of patients develop fistulae, but unclear aetiopathogenesis impacts treatment outcomes, quality of life, and healthcare costs. Chronic granulomatous disease (CGD) is a monogenic condition caused by pathogenic variants in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes which can present as CD-like colitis, abscesses, and immunodeficiency. Given CD’s genetic and phenotypic similarities with CGD, we hypothesised that NADPH oxidases may contribute to CD phenotypes, specifically in relation to fistulating disease behaviour.

Aims & Methods

This study explores the role of genetic variation in NADPH oxidases in CD patients (Southampton IBD cohort) using a per-patient, per-gene deleteriousness score (GenePy) to determine whether CD fistulating disease behaviour can be predicted and establish any potential epistatic interactions between genetic variation of subunits of the NAPDH oxidase complexes relevant to CD. Key NADPH oxidase protein-coding genes involved in CD were identified via literature review. Protein-protein interaction databases were used to collate a comprehensive network of potentially implicated genes. To determine subgroups of patients with differing genetic variation in the NAPDH oxidase genes we employed a principal component analysis (PCA), followed by hierarchical clustering of patients using GenePy scores, with optimal cluster numbers determined by silhouette scores. Cluster enrichment for fistulating disease was explored using Fisher’s exact test. To identify genes driving separation between CD patients we assessed differences in GenePy scores for the top PCA gene drivers between fistulating and non-fistulating subgroups using a Mann-Whitney U-test. Mutational profile characterisation include potential gene-gene interactions were evaluated via Spearman correlations. Multiple test correction was applied.

Results

Twenty-nine protein-coding genes were analysed. Clustering patients by GenePy scores for these genes after PCA resulted in distinct clusters, but no significant association between fistulating phenotype and cluster assignments was observed. However, significant differences between the GenePy scores of the top 5% of fistulating and non-fistulating groups were found for NOX3 (p = 0.016) and DUOX2 (p = 0.001), with fistulating patients having lower GenePy score for these genes, indicating these genes may drive a proportion of inflammatory CD behaviour.
Four gene pairs were significantly correlated (Table 1), indicating potential epistasis within NADPH oxidase complexes for patients with CD. High deleteriousness scores in multiple genes within a complex may indicate oligogenic contribution to a disease phenotype within individuals.

Conclusion

NADPH oxidase genes, and epistatic interactions between them, may modify the risk of fistulating CD and drive disease phenotype in a proportion of patients.

Disclosure

JJA is a scientific advisory board member for Orchard Therapeutics

Clinical Case Summary

A 54-year-old male with chronic myeloid leukemia (CML) diagnosed in May 2015, on Imatinib since April 2023, presented in October 2024 a severe anemia (Hb 5.2 g/dL [13-17]). Investigations done at that time, including bone marrow analysis, hemolysis workup and a FIT test were normal. An abdominal CT scan was also done at that time and was also normal.. In December 2024, the patient reported two weeks of melena. A bidirectionnel endoscopy didn’t show any lesion. CT scan revealed hepatomegaly and gallstones, without any GI mass.
Video capsule endoscopy showed active jejunal bleeding without being able to identify the underneath lesion. Enteroscopy revealed two ulcerated jejunal lesions of around 2 cm in diameter with an adherent clot, one meter from the papilla, [Figure 1,2]. Surgical resection was then performed [Figure 3]. Histology confirmed epithelioid angiosarcoma with submucosal infiltration, numerous mitoses, endolymphatic tumor emboli, and ERG+, cytokeratine AE1/AE3+ immunoprofile. Resection margins were clear; 0/3 lymph nodes were involved. [Figure 4a-b-c-d] As part of the metastatic workup, brain MRI showed multiple cerebral metastases.
Following the diagnosis, the treatment plan consisted of paclitaxel in combination with bevacizumab (Avastin).
This case illustrates the diagnostic challenge of unexplained anemia in hematologic patients, particularly when standard evaluations fail to identify a clear cause. In this instance, gastrointestinal bleeding ultimately revealed a rare small bowel malignant lesion—epithelioid angiosarcoma. While epithelioid angiosarcoma has no established association with chronic myeloid leukemia (CML) or its treatment, it is worth noting that the use of tyrosine kinase inhibitors may obscure the clinical presentation of angiosarcoma. This is due to their antiangiogenic effects, which can alter vascular structures and potentially delay diagnosis. Therefore, high clinical suspicion remains essential.

References

Figure 1,2 : Enteroscopy revealing ulcerated jejunal lesion with an adherent clot. Images obtained during enteroscopy performed at Hôtel-Dieu de France University Hospital, Beirut, Lebanon.
Figure 3 : Resected jejunal segment showing two hemorrhagic polypoid tumors, one marked with a hemostatic clip. The lesions correspond to an ulcerated angiosarcoma. Image obtained post-surgical resection at Hôtel-Dieu de France University Hospital, Beirut, Lebanon.
Figure 4a : Histological appearance of epithelioid angiosarcoma H&E stain, high magnification
Figure 4b : Histological appearance of epithelioid angiosarcoma H&E stain, intermediate magnification
Figure 4c : Histological appearance of epithelioid angiosarcoma H&E stain, low magnification
Figure 4d : Histological appearance of epithelioid angiosarcoma ERG nuclear immunostain, intermediate magnification
Figure 4e : Histological appearance of epithelioid angiosarcoma Cytokeratin AE1/AE3 immunostain, intermediate magnification

Introduction

Indeterminate biliary strictures pose a significant diagnostic challenge, as they can result from a wide spectrum of both benign and malignant conditions. Differentiating between these is crucial due to different management strategies. Conventional methods like endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology have limited sensitivity, often leading to repeated procedures and delays in treatment. Peroral cholangioscopy (POC) offers direct bile duct visualization and targeted biopsies, improving diagnostic accuracy. Modern systems, like the SpyGlass™ DS, enhance procedure feasibility and image quality.

Aims & Methods

Aims: The aim of our study is to assess the effectiveness of single-operator peroral cholangioscopy system (POCS) with its digital version SpyGlass^TM Direct Visualization System with SpyBite biopsies as a promising modality for accurate diagnosis of biliary strictures.
Method: We performed a two-center retrospective analysis of prospective database from March 2019 to March 2025. Each patient underwent peroral cholangioscopy using SpyGlass^TM Direct Visualization System with SpyBite biopsies for the diagnosis of indeterminate biliary strictures.

Results

We identified 162 patients who underwent peroral cholangioscopy during the study period (96 males and 66 females). The medium age of the patients was 63.04 years. There was 100 % technical success of the procedure. All patients underwent POCS due to indeterminate biliary strictures. Before the procedure CT scan was performed and positive for biliary stenosis in 115 (70.9%) of the cases. The biliary stenoses were located as follows: 20 (12.3%) in the distal common bile duct, 29 (17.9%) in the proximal common bile duct, 102 (62.9%) at the hepatic hilum and 11 (6.7%) in the intrahepatic bile ducts.
Benign disease was diagnosed in 39 (24.07 %) of the patients. Visual impression for malignant desease (at least one of the following- tortuous dilated vessels, friability and easily bleeding, infiltrative stricture, polipoid mass, nodular eleveted lesion, vegetative mass, fish-egg lesion, finger - like villiform lesion and irregular papillary or granular lesion) was found in 123 (75.9%) of the patients. The most reliable correlation with malignancy was found to be the presence of infiltrative strictures - 113 (69.7%) patients. A final diagnosis of cholagiocarinoma was established in 84
(51.8%) of them. In 39 (24.07%) patients, no tumor cells were found in the specimen. Visual impression accuracy with SpyGlass was 100% (with 100% sensitivity and 100% specificity). SpyBite biopsies accuracy was 69.05 % (with 68. 3% sensitivity and 100% specificity).

Conclusion

POC has proven valuable in evaluating indeterminate biliary strictures, offering advantages over ERCP by allowing real-time visualization and targeted biopsies. Our study supports POC's superior accuracy, especially in identifying malignant lesions, with visual impression achieving up to 100% sensitivity and specificity. However, POC adoption is limited by operator expertise, the need for standardized interpretation, and availability. While adverse events are rare (<10%), careful patient selection is essential. In conclusion, POC holds substantial promise as a key diagnostic tool for indeterminate biliary strictures, with ongoing improvements enhancing its clinical role.

Disclosure

No conflict of interest

Clinical Case Summary

This case report describes the clinical history of a 59 years-old female with a delayed diagnosis of primary biliary cholangitis (PBC) and celiac disease (CeD), ultimately requiring orthotopic liver transplantation (OLT). In June 2021 the patient developed weight loss, fatigue, anorexia, diarrhea, and generalized itching. As the patient showed progressive worsening of symptoms, an ultrasound scan was performed in May 2022 revealing hepato-splenomegaly, ascites and cholelithiasis, which required hospitalization. Laboratory tests showed hyperbilirubinemia, elevated liver enzymes with a cholestatic pattern, thrombocytopenia, and anemia; serology was positive for antimitochondrial (AMA) and antinuclear antibodies (ANA) and abdominal MRI confirmed intrahepatic bile duct alterations consistent with PBC. Persistent diarrhea and weight loss despite treatment with ursodeoxycholic acid and cholestyramine, required further evaluation for CeD. High tissue transglutaminase antibody levels and duodenal villous atrophy (3B according to Marsh-Oberhuber Classification) confirmed the diagnosis. A gluten-free diet (GFD) was started with incomplete adherence; the patient’s liver function further deteriorated, leading, in October 2023, to an acute on chronic decompensation with ascites and jaundice (Child-Pugh C13 and MELD 32). She eventually underwent successful OLT via piggyback technique. One year after transplant, the patient showed a significant clinical improvement, resolution of diarrhea and itching associated with better adherence to a GFD, although sarcopenia and nutritional deficiencies persisted. This report underscores the critical need for early diagnosis, screening for other autoimmune diseases, strict dietary adherence, regular follow-up, as well as a multidisciplinary management, in patients with PBC and CeD to prevent severe liver dysfunction and improve outcomes.

Figure 1. Trend of liver function markers (AST, ALT, GGT, ALP), MELD, Child-Pugh since PBC diagnosis

References

1. Kingham JG, Parker DR. The association between primary biliary cirrhosis and coeliac disease: A study of relative prevalences. Gut 1998;42(1)

2. Jena A et al. Liver abnormalities in celiac disease and response to gluten free diet: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2023 Jan;38(1):11-22. doi: 10.1111/jgh.16039.

3. Yang J et al.. Prevalence and effect on prognosis of sarcopenia in patients with primary biliary cholangitis. Front Med (Lausanne). 2024 Feb 29;11:1346165. doi: 10.3389/fmed.2024.1346165

4. Al-Toma et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019 Jun;7(5):583-613. doi: 10.1177/2050640619844125.

5. European Association for the Study of the Liver, EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017 Jul;67(1):145-172. doi: 10.1016/j.jhep.2017.03.022. Epub 2017 Apr 18. PMID: 28427765.