Introduction

Fatigue is highly prevalent in patients with Inflammatory bowel disease (IBD)and associated with reduced quality of life. However, effective treatments for IBD fatigue are lacking.

Aims & Methods

We aimed to assess the real-world efficacy of modafinil – a stimulant medication – on fatigue in IBD patients. The was a prospective evaluation in a tertiary IBD centre in the UK. Adults with a confirmed diagnosis of IBD, who were fatigued for at least 6 months, were referred for fatigue evaluation using the Inflammatory Bowel Disease Fatigue Self-Assessment Scale (IBD-F). The IBD-F includes 5 questions scored 0-4 using a Likert scale to identify fatigue. Scores range from 0-20 and scores ≥11 denote severe fatigue.
After treating organic causes of fatigue (anaemia, B12 deficiency, hypothyroidism, mucosal inflammation) and excluding contraindications, patients with a baseline IBD-F score ≥11 were offered modafinil. Modafinil was started at 100mg daily and titrated in 100mg increments to a maximum of 400mg daily if needed. If unable to tolerate 100mg, dosage was reduced to 50mg.
Patients were followed up until week 12 or drug withdrawal. IBD-F scores were reviewed at 12 weeks and compared to baseline. A clinically significant fatigue improvement was a reduction in the IBD-F score ≥3¹. Any patient who withdrew drug before 12 weeks was regarded as having severe fatigue at follow up.
Descriptive statistics were presented as means with standard deviation [SD]. A paired t-test was used to assess change in IBD-F scores from baseline with 5% significance level used.

Results

Seventy-two patients (50% male) were included with a mean age of 38 (SD 11.1) years . Of these, 53 (74%) had Crohn’s and 19 (27%) had UC with a mean disease duration of 13.2 (10.4) years (Table 1). The cohort showed refractory disease with 23 (32%) of patients having used at least 3 biologics, 24 (33%) had a stoma and 41(57%) had at least one bowel resection. The most common total modafinil dose was 200mg. Dosages ranged from 50mg to 400mg per day.
Both UC (15.9 [SD 2.58]) and Crohn’s (15.0 [2.31]) had similar mean (SD) baseline IBD-F scores. After treatment with modafinil, there was a statistically significant improvement in mean IBD-F score from baseline 15.3 [SD 2.38] to 10.4 [SD 3.83] (p<0.0001). There was no difference in the score improvement between UC and Crohn’s p=0.29. No difference was observed between those with and without irritable bowel syndrome (p=0.35). At follow up, 53 (74%) had a clinically significant improvement in fatigue and 38 (53%) were no longer severely fatigued.
Nine patients (13%) reported side effects: headache (n=5), and anxiety, mood changes, nausea, and visual issues (n=1 each). Three patients withdrew before the 12 week follow up. No serious adverse events were recorded.

Table1

Demographic Data	n =72 (%)
Male Female	36 (50) 36 (50)
Age:	mean 38 [SD 11.12] years
UC Crohn's	19 (26) 53 (74)
Disease Duration:	mean 13.2 [SD 10.39] years
Stoma	24 (33)
IBS	6 (8)
Smokers Ex smokers Non smokers	7 (15) 14 (31) 22 (49) n=45
No. of biologics used 0 1 2 3 4+	14 (19) 19 (26) 16 (22) 11(15) 12 (16)
Steroid use	25 (35)

Conclusion

In this real-world evaluation, modafinil was associated with a statistically significant improvement in fatigue in patients with mostly refractory IBD. Modafinil was generally well tolerated. Randomised, placebo-controlled trials of modafinil for IBD fatigue are now warranted.

References

1 Nocerino A, Nguyen A, Agrawal M, Mone A, Lakhani K, Swaminath A. Fatigue in Inflammatory Bowel Diseases: Etiologies and Management. Adv Ther. 2020;37(1):97-112. doi:10.1007/s12325-019-01151-w

Clinical Case Summary

We report a case of Intrahepatic Cholestasis of Pregnancy (ICP) leading to a rejections of a living, related donor liver two years after the liver transplantation (LT). The 36yo patient underwent LT in November 2021 in Mongolia due to a HBV/HDV related liver cirrhosis. Until August 2024, she had normal test results when she presented with severe pruritus and jaundice at 16-17th week of her second pregnancy. The ICP was diagnosed after elevated total bile acids were detected. A medical pregnancy termination was induced with subsequent three sessions of plasmapheresis. The patient's condition deteriorated further before she received her second living, unrelated donor LT in December 2024.
.

	2023.07.03- prior to pregnancy	2024.08.18- during the pregnancy	2024.09.30- A month after termination	2024.11.04	2025.02.02- Two months after re-transplantation
Total bilirubin (mg/dL) /norm 0-1.2/	1.5 N	17.6 H	20.2 H	40.6 H	0.73 N
GOT/GPT (IU/mL) /norm 0-40/	11.3/18.3 N	265.3/196.1 H	79.5/77.1 H	262.5/113.1 H	6.2/7.6 N
Total bile acids (umol/mL) /norm 0-10/		170.2 H	332 H		7 N

The explant histology stated a massive hepatocellular necrosis (fulminant), total bile duct loss, massive cholestasis (canalicular and intracellular), allograft arteriopathy: Foamy histiocytes in the intimal artery, Arteriosclerosis and Lumen narrowing. No genetic test was performed , either prior or after the LTs. The final diagnosis: An Intrahepatic Cholestasis of Pregnancy leading to a liver graft rejection.
The ICP is a relatively common pregnancy related condition (0.2-2% of pregnancies in Europe and Americas¹) that presents with jaundice and pruritus. The condition usually improves after delivery/termination. In rare cases elevated serum bile acid levels lead to fetal abnormalities or loss of pregnancy. Since the patients condition did not improve after the pregnancy termination in September, 2024, Progressive Familial Intrahepatic Cholestasis (PFIC) was suspected when she admitted her first pregnancy was also complicated by ICP. Better history taking is needed to prevent graft rejection due to bile acid transport dysfunction.

References

1- Williamson, C. and V. Geenes, Intrahepatic cholestasis of pregnancy. Obstet Gynecol, 2014. 124(1): p. 120-133

Introduction

Primary sclerosing cholangitis (PSC) is a major type of autoimmune cholestatic liver disease with unknown etiology, characterized by cholestasis, abnormal biliary epithelial homeostasis, biliary tract fibrosis and consequently liver dysfunction^1,2. Notably, PSC further elevates the risk of developing cholangiocarcinoma³. Investigating the underlying causal factors could contribute to the development of novel therapeutic strategies, thereby mitigating the burden on public health systems imposed by these conditions.
Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases. The toxicity of bile acids is associated with the severity of cholestatic diseases^4,5. Among all BA components, hydrophobic BAs such as chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)⁶ are considered the main toxic components to the bile duct epithelium and hepatocytes. Besides, glycochenodeoxycholic acid (GCDCA) has been used to model BA toxicity both in vivo and in vitro⁷. The clinical usefulness of plasma BA in cholestatic diseases was studied via BA profiling in cholangitis cohorts, and the clinical utility was analysed^4,8. Nevertheless, no large-scale epidemiology studies have identified the causal relationship between individual components of BA and the pathogenesis of cholangitis, especially the sequence between changes in BA composition and disease onset.
In this study, we extracted summary statistics of 32 plasma BA components from the largest metabolome GWAS dataset to date⁹ as exposures and performed two-sample MR using 2 datasets of PSC as outcomes, followed by reverse MR, to assess the causal relationship between BAs and the pathogenesis of this disease.

Aims & Methods

We aimed to identify causal bile acid components on PSC using mendelian randomization. Summary statistics for primary sclerosing cholangitis were retrieved from European Bioinformatics Institute and FinnGen Consortium, and plasma bile acid components data were obtained from European Bioinformatics Institute. BA profiles of PSC patients by GC-MS were retrieved from published researches. Statistical analyses used the inverse variance weighted(IVW), weighted median(WM), maximum likelihood(ML) and MR-Egger algorithm, followed by various sensitivity analyses and reliability evaluation.

Results

Plasma level of glycochenodeoxycholate glucuronide(GCDCG) is negatively correlated with primary sclerosing cholangitis (IVW: OR=-0.12, p=0.0269 in EBI dataset, OR=-0.38, p=0.0299 in FinnGen dataset). No reverse causal effect was identified(IVW: p=0.7067 in EBI dataset, p=0.5158 in FinnGen dataset). GCDCG was decreased in bile of patients with PSC compared with healthy controls (logFC=-2.09, p=0.010).

MR type	data sources	outcome	exposure	method	OR	p value	Cochrans Q p value	Egger intercept p value
forward	EBI GWAS catalog	PSC	GCDCG level	ML	-0.1170	0.0135
				MR Egger	-0.1960	0.0242	0.4143	0.1469
				WM	-0.1813	0.0007
				IVW	-0.1158	0.0269	0.2753
	FInnGen			ML	-0.3880	0.0299
				MR Egger	-0.6690	0.0768	0.8872	0.3418
				WM	-0.5047	0.0294
				IVW	-0.3836	0.0299	0.8663
reverse	EBI GWAS catalog	GCDCG level	PSC	IVW	0.0054	0.7067	0.5615

Conclusion

Our findings provide evidence regarding the risk of primary sclerosing cholangitis for individuals with low level of plasma glycochenodeoxycholate glucuronide, and targeting the transformation of glycochenodeoxycholate into its glucuronide may be a novel therapeutic strategy to primary sclerosing cholangitis.

References

1. Dyson JK, Beuers U, Jones DEJ, et al. Primary sclerosing cholangitis. Lancet 2018;391(10139):2547-2559.
2. Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2023;21(8):2076-2087.
3. Tham EKJ, Lim RY, Koh B, et al. Prevalence of Chronic liver disease in Cholangiocarcinoma: a Meta-Analysis. Clin Gastroenterol Hepatol 2024.
4. Mousa OY, Juran BD, McCauley BM, et al. Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation. Hepatology 2021;74(1):281-295.
5. Perreault M, Białek A, Trottier J, et al. Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction. PLoS One 2013;8(11):e80994.
6. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999;159(22):2647-58.
7. Du Y, Khandekar G, Llewellyn J, et al. A Bile Duct-on-a-Chip With Organ-Level Functions. Hepatology 2020;71(4):1350-1363.
8. Tietz-Bogert PS, Kim M, Cheung A, et al. Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis. International Journal of Molecular Sciences 2018;19(10):3188.
9. Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nature Genetics 2023;55(1):44-53.

Introduction

Radioactive phosphorus (³²P) is an innovative therapy for locally advanced pancreatic cancer that is implanted through endoscopic ultrasound (EUS). Pancreatic cancer is the fourth cause of death and is responsible for 7% of all deaths caused by cancer. Nowadays the improvement of chemotherapy and the usage of combination therapies led to a better prognosis and studies showed an improvement of the survival parameters (OS, Free Progression Survival). One of the most innovative therapies is the implantation of radioactive phosphorus-32 which is a type of brachytherapy. It is indicated for the treatment of patients with Locally Advanced Pancreatic Cancer (LAPC) in combination with gemcitabine-based chemotherapy.

Aims & Methods

The primary goal of this study is to determine the safety of the intra-tumoral implantation of radioactive phosphorus (³²P) through EUS and the complications of the procedure of implantation. The secondary goals are to determine the Local Disease Control Rate (LDCR) at 16 weeks and the effectiveness of the implantation of radioactive phosphorus by measuring Overall Survival (OS), Progression Free Survival (PFS) and Local Progression Free Survival (LPFS). We currently have made the implantation in eight patients with similar clinical and demographic features who suffer from locally advanced pancreatic cancer. They receive gemcitabine-based chemotherapy in combination with an intra-tumoral therapy with radioactive phosphorus (³²P) through a 22-gauge FNA needle guided by EUS. The adverse events of the implantation are evaluated by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The LDCR is evaluated at 16 weeks and the alteration of Tumor Volume every two months for the first year after implantation and every three months the second year after implantation according to RECIST 1.1.

Results

The eight procedures (median age of patients: 68,5 years) were unremarkable and no complication during the procedure was noted. The patients did not have any major adverse events during the day of the procedure. Five out of eight patients (62,5%) revealed mild abdominal pain on the second day which recovered with typical pain killers. The LDCR, for all patients, at 16 weeks, was 100%. Two of the patients had a major reduction in the tumor so it was resectable. The operations were without any complications and the pathology test showed R0 resection. Two patients died after 12 months of follow up (one patient showed progression disease after 10 months from implantation and one patient had stable disease until death) and one patient revealed progression of disease after 12 months and is still alive after 15 months of follow up. Three patients have stable disease after 6 months of follow up, even though a slight reduction of the tumor has been noted. The six patients (including the two that died and not including the two that underwent surgery) have been followed up for 6 to 15 months, depending on time of implantation. The median Progression Free Survival for these six patients is 7 months (max 12 months – min 6 months) and the median Local Progression Free Survival is 6 months (max 12 months – min 6 months).

Conclusion

We must include more patients to conduct more useful results, but the initial results look promising.

References

1.Wungki P, Akhil C, Eileen M. Pancreatic Cancer: A Review. JAMA. 2021 September 07;326(9):851-862.
2.OncoSil System: Instruction for Use
3.Audrey V, Joseph H, Rich S, et al. Pancreatic cancer. Lancet. 2011 August 13; 378(9791): 607-620. doi: 10.1016/S0140-6736(10)62307-0.

Disclosure

​None to report