Introduction

The new nomenclature of Non alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated steatotic liver disease (MASLD), has an excellent concordance and 99% of individuals with NAFLD meet MASLD criteria. MASLD is becoming the most rapidly increasing contributor to the disease burden related to adverse liver outcomes, including cirrhosis, liver failure, and HCC. To curb this rising tide of MASLD (38.2% global prevalence), an early comprehensive and efficient management strategies are very crucial. Saroglitazar, a novel dual PPAR α/γ agonist operates through a multifaceted mechanism of action, targeting key pathways driving the progression of MASLD, and have shown benefits at different stages of disease ranging from early to advance fibrosis and compensated cirrhosis.

Aims & Methods

We tried to evaluate the effect of Saroglitazar in MASLD associated early fibrosis, in a population where majority did not have diabetes and hypertension at baseline.
A prospective, real world study was conducted at a single centre setting in North India with 67 patients showing ultrasonographic evidence of fatty liver changes and dyslipidemia. Transient elastography was performed to reliably exclude advanced liver disease and treatment progression at 3 and 6 months after Saroglitazar 4 mg OD prescription. The Controlled Attenuation Parameter (CAP) and liver stiffness measurement (LSM) were assessed as primary treatment endpoints along with other markers of liver function and metabolic health as secondary efficacy parameters. Changes were evaluated using paired t-tests, from baseline to the 12 and 24 week mark. This rigorous methodology allowed for a comprehensive assessment of Saroglitazar's impact on both liver health and metabolic parameters.

Results

The 67 patients, who followed the study inclusion criteria and treated with Saroglitazar 4 mg OD, were evaluated on primary and secondary efficacy parameters. They had the mean age 50.34 ±11.69 and mean body weight 82.1 ±11.9. Among them, 61.2% are males, 88.1% non diabetic, 89.6% non hypertensive, and 83.6% are not having any family history of NAFLD. 57.8% of them had F0-F1 fibrosis and 34.4% had F2 fibrosis at baseline. The mean reduction in CAP was 34.7 (p<0.001) and 38.7 dB/m (p<0.001) and mean reduction in LSM was 0.53 (p=0.043) and 1.31 Kpa (p<0.001), respectively at 12 and 24 weeks (n=32). A significant and consistent reduction in AST, ALT, TG, LDL and HbA1c was also seen. No new safety signals were observed.

Table: Absolute and percentage mean changes in Primary and secondary study parameters at 12 and 24 weeks

Conclusion

Treatment with Saroglitazar 4 mg significantly reduces liver stiffness and steatosis, improves liver enzymes, and other metabolic parameters like serum glucose and lipid profile. It could be a crucial treatment component for an early comprehensive and efficient management of MASLD and helpful in curbing the rising tide of global MASLD burden. Saroglitazar treatment was safe.

References

1. Targher G, Byrne CD, Tilg HMASLD: a systemic metabolic disorder with cardiovascular and malignant complicationsGut 2024;73:691-702.
2. Lei Miao, Giovanni Targher, Christopher D. Byrne, Ying-Ying Cao, Ming-Hua Zheng, Current status and future trends of the global burden of MASLD, Trends in Endocrinology & Metabolism, 2024,ISSN 1043-2760, https://doi.org/10.1016/j.tem.2024.02.007.
3. Soto A, Spongberg C, Martinino A, Giovinazzo F. Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond. Biomedicines. 2024; 12(2):397. https://doi.org/10.3390/biomedicines12020397

Introduction

Celiac disease, a chronic autoimmune enteropathy caused by exposure to gluten in genetically predisposed individuals, is characterized by a broad clinical spectrum often with multisystem involvement. Symptoms related to the reproductive system include delayed menarche, early menopause, fertility disorders, miscarriages, and prematurity.

Aims & Methods

To study the impact of celiac disease on fertility in a female Greek population. A retrospective review of all patient records from the celiac disease outpatient clinic at our hospital.

Results

Medical histories of 231 female patients were reviewed (69% of the total patient population) with a mean age of 44.3 years and a mean age at diagnosis of 35.3 years. The mean age of menarche was 12.7 years. Menstrual irregularities were reported in 27% (20% instability, 7% dysmenorrhea). A total of 28% (65/231) were in menopause, with an average age of menopause onset at 50.7 years. A history of miscarriages was recorded in 15% of all women (35/231), but in 29% of women in menopause (19/65). 82% (53/65) of women in menopause had children, with 98% (52/53) having been pregnant before the diagnosis of the disease. Among all women who gave birth, only 12/113 (11%) had been diagnosed before pregnancy. 56% (63/113) and 44% (50/113) had a vaginal delivery and cesarean section, respectively. Pregnancy complications were recorded in 24 women (18 preterm births, 15 low birth weight infants, 1 intrauterine death).

Conclusion

Women with celiac disease tend to have relatively late menarche and an increased rate of miscarriages. However, the disease does not seem to significantly affect fertility.

References

1.Ehud Galron MD, Rayna Boyarsky MD,Ido Sold MD, Chen Ben David MD,and Eyal Gal MD,Interactions between celiac disease and pregnancy:A literature review, Isr Med Assoc J.2023 Dec;25(12):830-835
2.Giovanni Casella et. Al. Celiac disease and obstetrical-gynecological contribution, Gastroenterol Hepatol Bed Bench. 2016 Autumn; 9(4): 241–249.
3.Stephanie M. Moleski et. Al., Increased rates of pregnancy complications in women with celiac disease, Annals of Gastroenterology (2015) 28, 236-240
4.Nafeesa N. Dhalwani et Al., Women With Celiac Disease Present With Fertility ProblemsNo More Often Than Women in the General Population, Gastroenterology 2014;147:1267–1274

Clinical Case Summary

Background: Brucellosis is a zoonotic illness with high morbidity rates in Armenia. According to National Institutes of Health's Annual Statistical Records, the number of cases with Brucellosis diagnosed in Armenia was 362 in 2017 and 201 in 2018. In some cases co-infection of Brucellosis with other diseases is seen. The aim of the case report is to discuss the challenges of management of patient with Brucellosis and Hepatitis C (HCV) infection.
Case presentation: A 59-year-old male was admitted to Intensive Care Unit with upper GI bleeding, the patient was diagnosed with liver cirrhosis of mixed etiology (alcohol, HCV), Child-Pugh C class. After 2 months patient experienced an increase in body temperature-39^oC, back pain, neuropathy and paresthesia. He was tested for Brucellosis, positive (1:200) Wright-Hedelson agglutination test and serology (high levels of IgG and IgM) confirmed diagnosis. Many drugs can be used for the management of Brucellosis but Gentamycin and Streptomycin were contraindicated in decompensated cirrhosis, the patient was allergic to Sulfamethoxazole, Rifampicin can’t be combined with Sofosbuvir. Only options left were Doxycycline and Ciprofloxacin. So, we made a decision to initiate Ciprofloxacin monotherapy for 4 weeks, until the HCV elimination therapy would be completed. After the HCV PCR came negative, Rifampicin, Doxycycline were added to Ciprofloxacin for 3 months for brucellosis management. During this time the patient was closely monitored. All the complaints were alleviated, lab tests normalised, with HCV SVR(Sustained Virologic Response)12 and SVR24.
Conclusion: Until now, there was no case described in the literature of the combined management of decompensated cirrhosis and spinal brucellosis, which ends in compensation without liver transplantation. This case serves as a reminder of the importance of a comprehensive and individualized approach to patient care, particularly in the context of complex, comorbid medical conditions.

References

• Polaris Observatory HCV Collaborators. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. Lancet Gastroenterol Hepatol. 2022 May;7(5):396-415. doi: 10.1016/S2468-1253(21)00472-6. Epub 2022 Feb 16. PMID: 35180382.
• Singh, S., Hoque, S., Zekry, A. et al. Radiological Diagnosis of Chronic Liver Disease and Hepatocellular Carcinoma: A Review. J Med Syst 47, 73 (2023). https://doi.org/10.1007/s10916-023-01968-7
• Mohamed AA, Lu XL, Mounmin FA. Diagnosis and Treatment of Esophageal Candidiasis: Current Updates. Can J Gastroenterol Hepatol. 2019 Oct 20;2019:3585136. doi: 10.1155/2019/3585136. PMID: 31772927; PMCID: PMC6854261.
• Tu L, Liu X, Gu W, Wang Z, Zhang E, Kahar A, Chu G, Zhao J. Imaging-Assisted Diagnosis and Characteristics of Suspected Spinal Brucellosis: A Retrospective Study of 72 Cases. Med Sci Monit. 2018 Apr 29;24:2647-2654. doi: 10.12659/MSM.909288. PMID: 29705812; PMCID: PMC5946739.
• M. Reza Hasanjani Roushan, S. Ebrahimpour. Human brucellosis: An overview. Caspian J Intern Med. 2015. PMC4478120
• M.J. Corbel. Brucellosis in humans and animals. World Health Organization 2006. https://iris.who.int/bitstream/handle/10665/43597/WHO_CDS_EPR_2006.7_eng.pdf?sequence=1
• Gamze Kalin Unuvar, Aysegul Ulu Kilic, Mehmet Doganay. Current therapeutic strategy in osteoarticular brucellosis. Northern Clinics of Istanbul. 2019; doi:10.14744/nci.2019.05658
• Ljubas D, Lalovac M, Vince A, Papic N. Brucellosis, a forgotten cause of hepatitis in travellers. Journal of Travel Medicine. 2020;28(3). doi:10.1093/jtm/taaa218

Introduction

Barrett’s esophagus (BE), the major precursor of esophageal adenocarcinoma (EAC), is a condition where the normal stratified squamous esophageal epithelium undergoes transdifferentiation into the specialized, intestinal-like epithelium. This reprogramming, also termed ‘paligenosis’, is predominantly caused by gastroesophageal reflux disease (GERD)¹. On the other hand, hydrogen sulfide (H₂S) next to carbon monixide (CO) is an important endogenous gaseous mediator. H₂S is biosynthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). Both, H₂S and CO have been shown to maintain gastrointestinal (GI) integrity^2,3,4. However, the contribution of gaseous mediators signaling to esophageal transdifferentiation process is overlooked.

Aims & Methods

Thus, in this study we aimed to explore the role of H₂S bioavailability in mTOR-dependent paligenosis induced by chronic epithelial injury. Furthermore, we evaluated the relationship between GERD, the barrier function of cultured cells, and the pattern of selected components involved in the formation of the tight junctions (TJs) and responsible for epithelial barrier integrity.
We implemented an animal model of GERD, based on Male Wistar rats with esophagogastroduodenal anastomosis (EGDA) treated i.g. for 8 weeks with vehicle or with H₂S- releasing chemicals: GYY4137 (5.0 mg/kg)/NaHS (1.0 mg/kg) or CTH/CBS inhibitors: PAG (15 mg/kg)/AOAA (11 mg/kg). In parallel, we employed optimized in-vitro GERD model based on human-derived esophageal epithelial (EPC2) cells +/- CRISPR-Cas9-induced knockout of H₂S-producing enzymes that were treated with acidified bile mixture (BM) or with GYY4137/NaHS (100 µM). We evaluated activation of AKT/mTOR pathway by multiplex microbeads fluorescent assay and an expression of TJ-associated protein (ZO-1) and occludin by capillary immunoblotting. The barrier function of cultured cells was evaluated by measurement of transepithelial electrical resistance (TER).

Results

We observed that either chronic reflux in EGDA-rats and/or treatment of human esophageal cells with BM led to a slight or a significant activation of AKT/mTOR signaling pathway and its down-stream effector - p70S6K. Additionally, we observed that pharmacologically-derived H₂S reversed this effect, while inhibition of endogenous H₂S biosynthesis (pharmacological or induced by knockout of H₂S-producing enzymes) had either no effect or increased GERD-induced phosphorylation of AKT/mTOR pathway components. Moreover, we showed that ZO-1 is highly expressed in BM treated EPC2 cells and this was reflected by the increase in TER measurment. Level of occludin remained unchanged. We did not observe any changes in expression of ZO-1 and occludin after GYY4137 treatment; however, TER measurment decreased in comparison to BM treated cells. Selective knockout of H₂S-producing enzymes led to a decrease in ZO-1 protein content in comparison to wild-type cells.

Conclusion

We conclude that interventional enhancing or decreasing of H₂S bioavailability in esophageal epithelium respectively delay or accelerate the GERD-induced paligenosis process via regulation of the mTOR pathway. H₂S-prodrugs may provide a protective effect on the esophageal epithelium by substituting the phisiological defensive response of the tissue against GERD, which is reflected by an increase in the expression of ZO-1 and tightening of the cellular barrier.

References

1. Souza RF, Spechler SJ. Mechanisms and pathophysiology of Barrett oesophagus. Nat Rev Gastroenterol Hepatol 2022.
2. Fiorucci S, Distrutti E, Cirino G, Wallace JL. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 2006.
3. Magierowska K, Korbut E, Wójcik-Grzybek D, Bakalarz D, Sliwowski Z, Cieszkowski J, Szetela M, Torregrossa R, Whiteman M, Magierowski M. Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury. J Control Release 2022.
4. Magierowska K, Brzozowski T , Magierowski M. Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity. Pharmacol Res 2018.

[Funding: National Science Centre, Poland (UMO-2016/23/D/NZ4/01913, UMO-2019/33/B/NZ4/00616) and Statutory Grant (N41/DBS/000874), Jagiellonian University Medical College].

Introduction

Individuals with coeliac disease (CeD) commonly complain of persistent symptoms despite adhering to a gluten free diet (GFD). We analysed baseline data from the prospective pseudonymized German CeD Registry to identify factors associated with ongoing complaints.

Aims & Methods

​​​​​​After written informed consent, participants self-reported demographic, clinical and healthcare related information at baseline and yearly thereafter. Symptoms before diagnosis and during the four weeks prior to completing the baseline questionnaire were retrospectively assessed. Factors associated with symptoms after at least one year of gluten-free diet (GFD) were evaluated by multivariate logistic regression.

Results

From 11/2019 to 10/2021, 2164 participants provided baseline data: 78% were female, median age 36 years (range 1.1 to 93.2), median time since diagnosis 6.3 years (0 to 58.7), and median diagnostic delay (time from first symptom to diagnosis) 2.2 years (0 to 64.8). Most common symptoms before diagnosis included abdominal pain (83%), bloating (82%), fatigue (78%), and diarrhoea (71%). Individuals diagnosed in adulthood were more symptomatic compared to paediatric patients. Although 93.4% of participants reported improvement after diagnosis, a substantial proportion of those keeping a GFD >1year (n=1861, 86% of cohort) had ongoing symptoms. Factors associated with regularly experiencing above symptoms included female gender, having the same symptom before diagnosis, feeling insufficiently informed by their physician about CeD and implications for their daily life, and age at diagnosis (per decade), but not time since diagnosis (table).

Conclusion

Our findings revealed deficits in awareness, the diagnostic process, and post-diagnostic care. In this large cohort of patients with CeD we identified factors associated with persistence of symptoms despite keeping a GFD for at least one years. Early diagnosis, providing comprehensive education after confirmed diagnosis, and ensuring strict dietary adherence are pivotal for symptom resolution. A population-based mass-screening for CeD in childhood should be further explored. Implementing a multifaceted approach will enhance care for individuals with CeD and ultimately improve long-term health and well-being.

Introduction

Celiac disease (CD) is an autoimmune enteropathy induced by the ingestion of gluten in genetically predisposed individuals. Although its clinical expression is most often digestive, extra-digestive manifestations can occur, among which thromboembolic complications, although rare, deserve particular attention.
The aim of this study is to describe the profiles of coeliac patients with thromboembolic complications, analyze their clinical, paraclinical and etiological characteristics, and discuss the underlying pathophysiological mechanisms.

Aims & Methods

This is a retrospective, descriptive, monocentric study conducted in the hepato-gastroenterology department of Ibn Sina Hospital in Rabat over a 30-year period, from 1995 to 2025. The records of 344 patients followed for celiac disease were reviewed. Patients with one or more documented thromboembolic complications during follow-up were included in the study. Clinical, biological, endoscopic and histological data were collected and analyzed.

Results

Of a total of 344 patients followed for celiac disease in the department, 5.5% (n=19) developed a thromboembolic complication during follow-up. The population concerned was predominantly female, with 89.5% women (n=17) versus only 10.5% men (n=2). The mean age at the time of complication was 39.6 years, with a median of 35.5 years, and extremes ranging from 18 to 62 years.
Endoscopic exploration (oesogastro duodenal fibroscopy) in these patients showed lesions suggestive of celiac disease in 68.4% (n=12), while it was non-specific in 31.6% (n=6), and normal in 5.3% (n=1). Histologically, villous atrophy was found in all patients, with 78.9% (n=15) showing total atrophy (Marsh IIIc) and 21.1% (n=4) subtotal atrophy (Marsh IIIb).
As regards thromboembolic manifestations, portal vein thrombosis was the most frequent complication, observed in 57.9% of cases (n=11). It was followed by deep vein thrombosis of the lower limbs, reported in 15.8% of cases (n=3), and ischemic stroke in 10.5% (n=2). Isolated cases of thrombosis of the inferior vena cava, axillary vein and femoral vein were recorded, each accounting for 5.3% of cases (n=1).
The etiological study revealed hyperhomocysteinemia in 36.8% of patients (n=7) and protein C and/or S deficiency in 21.1% (n=4). In the remaining 42.1% of patients (n=8), the thrombophilia work-up was normal, suggesting that celiac disease itself was the cause of the thrombotic event.
Therapeutically, all patients were treated with oral anticoagulation. One patient required a vena cava filter because of the risk of bleeding on anticoagulation, and another underwent surgical treatment for axillary thrombosis. The outcome was favorable in all cases, with no recurrence or major complication during follow-up.

Conclusion

Thromboembolic complications in celiac disease are rare but potentially serious. This study highlights the predominance of women, the diversity of thrombotic localizations, and the possible involvement of hyperhomocysteinemia and C/S protein deficiencies. In almost half the cases, no thrombophilic cause has been identified, suggesting a role for celiac disease in the genesis of these events. Clinical vigilance is essential, particularly in cases of late diagnosis or poor compliance with the gluten-free diet.

Introduction

While wide-scale screening for celiac disease (CeD) is increasingly being considered, its overall benefits are not well established.

Aims & Methods

We investigated the general health at diagnosis and long-term outcomes in CeD patients identified through screening in a population-representative cohort. Comprehensive health data from individuals participating in the nationally representative Health 2000 survey (N=6,376) were analyzed using registry data and interviews. Additionally, blood was collected to measure tissue transglutaminase antibodies (TGA) and endomysial antibodies (EmA) if TGA was positive, as well as other laboratory parameters. Altogether, 3254 subjects participated in a follow-up study in 2011. Mortality among subjects in the Health 2000 cohort was evaluated at the 17-year follow-up using the national statistics registry.

Results

Ninety CeD patients were identified in 2000, of whom 54 participated in the follow-up in 2011 while on a gluten-free diet. At diagnosis, patients more often had pre-eclampsia (13% vs. 5%, p=0.016), and lower levels of hemoglobin (median 140 vs 143 g/L, p=0.046), ferritin (29 vs 68 ng/mL, p<0.001), total cholesterol (5.4 vs 5.9 mmol/L, p<0.001), apolipoprotein A1 (1.40 vs 1.57 g/L, p<0.001) and apolipoprotein B (1.16 vs 1.21 g/L, p=0.009) compared to seronegative population. The groups did not differ in age (48 vs 51 years, p=0.159), sex (females 62% vs 56%, p=0.205), BMI (26 vs 26, p=0.567), blood pressure (131/81 mmHg vs 132/82 mmHg, p=0.230), or the presence of other gastrointestinal diseases, cardiovascular and psychiatric diseases, osteoporosis, malignancies, or smoking and alcohol consumption. No significant changes in cholesterol or apolipoprotein levels, mental health, or health care utilization were observed among CeD patients during the 11-year follow-up. The patients had a lower mortality rate compared to non-CeD individuals after 17 years with borderline significance (14.1% vs. 25.6%, p=0.059).

Conclusion

Population-representative individuals with screen-detected celiac disease exhibit a more favorable metabolic profile, but have lower hemoglobin and iron levels and a higher prevalence of pre-eclampsia at diagnosis. Gluten-free diet does not appear to cause adverse effects. Screen-detected patients may also have a reduced long-term mortality, although further research is needed.