Introduction

Inflammatory bowel disease (IBD), comprising of Crohn’s disease and Ulcerative Colitis (UC), is a debilitating inflammatory disease of the gastrointestinal tract with no known cause. Although extensive work has linked numerous genetic loci to IBD, most of these associations remain poorly understood. In addition, some studies have associated IBD to metabolic diseases such as diabetes and non-alcoholic fatty liver disease (NAFLD), although the precise molecular and pathophysiological mechanisms underlying these associations are unknown.

Aims & Methods

The central objective of this study was to understand the molecular mechanisms underlying the associations between IBD and obesity related metabolic diseases. To address this research question, we used multiple mouse models of colitis (dextran sodium sulfate or DSS), DSS and Azoxymethane induced colitis associated colon cancer and Helicobacter hepaticus infection induced colitis in Il-10-/- mice) and high fat diet (HFD) and genetic models of obesity and obesity associated metabolic diseases. In addition, for mechanistic studies, we used chimeric mice generated through bone marrow transplantation as well as conditional knockout mouse models. Lastly, we employed CRISPR/Cas9 edited cells in vitro to understand the molecular mechanism.

Results

Employing multiple murine models of colitis, colitis-associated colon cancer (CAC) and obesity associated metabolic diseases, we have identified DUPD1, a phosphatase of unknown function, that links IBD with metabolic diseases. Specifically, Dupd1^-/-mice are protected from dextran sodium sulfate (DSS) and Helicobacter hepaticus induced colitis, and DSS/azoxymethane (AOM) induced CAC. Dupd1^-/- mice also exhibited protection against high fat diet (HFD) induced obesity and fatty liver disease and glucose intolerance. DUPD1 is highly expressed in the skeletal muscle. Indeed, using skeletal muscle specific conditional DUPD1 knockout mice (Dupd1^fl/flMyf6^Cre), we show that DUPD1 exerts its colitogenic effects from the skeletal muscle through modulation of autophagy, a pathway whose dysfunction is known to play a role in IBD. Importantly, a dual specificity phosphatase inhibitor (NSC-663284) inhibited DUPD1 enzyme activity and reduced DSS-induced colitis in wild type mice but not in Dupd1^-/-mice.

Conclusion

Our study identifies Dupd1 as a central gene that links IBD and obesity-associated metabolic diseases and suggests that it is a new therapeutic target in IBD, and obesity associated metabolic diseases.

Disclosure

Nothing to declare.

Introduction

Liver transplant is the only definitive treatment for chronic liver disease (CLD). Referral to a hepatologist for consideration for liver transplant should be made when a patient with CLD experiences a hepatic decompensation or has a MELD score ≥ 15. Failure to refer in a timely manner can result needing a liver transplant evaluation (LTE) in the inpatient setting while a patient is experiencing acute decompensation.

Aims & Methods

We aimed to compare the clinical presentation of patients undergoing LTE in the inpatient setting versus the outpatient setting to identify potential risk factors for requiring urgent evaluation. A list of all LTEs performed at our institution between 10/2017-8/2021 was obtained. Medical records were preliminarily reviewed for evaluation setting (Inpatient vs. Outpatients); evaluations for re-transplantation and acute liver failure were excluded. After all Inpatients (n=159) were identified, Outpatients (n=159) were selected at random to create a sample matched for age, gender, race, and ethnicity (n=318). Data were collected using our institutions electronic medical record and outside health records as obtained during LTE process. “Prior decompensations” refers to the number of the following clinical decompensations experienced prior to the time of LTE: ascites, hepatic encephalopathy (HE), variceal/acute UGIB, SBP and HRS. Categorical variables and continuous were compared between using Fisher’s Exact test, and student’s T test, respectively.

Results

Alcohol was the most common CLD etiology (42.1% Inpatient, 48.4% Outpatient). Inpatients tended to live further from our center than Outpatients (p=0.079). Inpatients had significantly higher MELD-Na scores (27.1 ± 8 vs. 13.3 ± 6; p<0.0001). Malnutrition was more common in 5.6 times more common in inpatients than outpatients (OR 5.6, 95% CI 2.9-10.8, p<0.001).. A similar proportion of patients had 1 hospitalization. But inpatients were 3 times as likely to have had ≥ 1 liver-related hospital admission prior to LTE (p<0.0001). Inpatients had significantly more prior decompensations than Outpatients prior to inpatient LTE (3.2 ± 1.4 vs. 1.8 ± 1.1, p<0.001), with the greatest differences in SBP and HRS.

Conclusion

Multiple liver-related hospitalizations and malnutrition may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

References

Multiple liver-related hospitalizations may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

Disclosure

D Devuni has received grant funding from Sequana Medical and receives grant support from the NIAAA (AA017986-11), both for research unrelated to this work.

Introduction

Endoscopic submucosal dissection (ESD) is the first-line treatment for superficial gastric lesions with a negligible or very low risk of lymph node metastasis. However, a permanent risk of developing metachronous lesions persists. We intend to analyze the risk factors associated with the development of metachronous lesions in a population of patients undergoing ESD.

Aims & Methods

Prospective cohort study conducted at a single centre, involving patients who underwent gastric ESD for lesions between 2017 and 2023, with a follow-up period of ≥ 6 months. Lesion characteristics were analyzed, including the rate of metachronous lesions, and logistic regression was performed to identify risk factors associated with the development of metachronous lesions.

Results

Included 78 ESDs performed on gastric epithelial lesions (59% female), with a mean age of 70.3±7.9 years. Regarding family history of gastric adenocarcinoma, 17.9% of patients had a first-degree relative. Among the analyzed lesions: 42.3% measured between 0-20mm, 57.7% ≥ 20mm; 12.8% were sessile, 71.8% flat and 15.4% depressed; 19.2% were located in the cardia, fundus or body, 21.8% in the incisura angularis and 59% in the antrum. Regarding histological findings: 42.3% low-grade dysplasia, 30.8% high-grade dysplasia, 23.1% intramucosal adenocarcinoma and 3.8% adenocarcinoma with submucosal invasion. Nine metachronous lesions (11.5%) were detected, with a median time of occurrence of 24 [13-32] months. In the analysis of risk factors, statistical significance was found for location outside the antrum (21.6% vs. 1.9%; p=0.002) and the presence of adenocarcinoma (23.8% vs. 7%; p=0.039), but not for size ≥20mm (13.7% vs. 5.1%; p=0.178) or ulceration of the lesion (9.1% vs. 10.1%; p=0.915). Logistic regression analysis revealed that only location outside the antrum had a significant risk for the development of metachronous lesions (OR 13.4; 95% CI: 1.4-127.1).

Conclusion

Given the permanent risk of developing metachronous lesions, the identification of associated risk factors is important as it may eventually allow for the adaptation of surveillance programs.

Introduction

Inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract, is caused by various factors, including genetic factors and environmental factors, as well as dysregulated immune responses. LMT503, a novel organic small-molecule compound, has the potential to suppress pro-inflammatory cells and induce anti-inflammatory cells by modulating their cell metabolisms. We evaluated the anti-inflammatory effects of LMT503 in a murine adoptive T cell transfer-induced colitis model.

Aims & Methods

This study was conducted to evaluate the anti-inflammatory effect of LMT503 in the murine chronic colitis model. Naïve CD4⁺CD25^-CD45RB^high CD62L^high T cells that were isolated from wild-type mice by flow cytometry based-method and transferred to Rag1 knock-out mice by intraperitoneal injection to induce murine adoptive T cell transfer-induced colitis. LMT503 was orally administrated (50mg/kg, 100mg/kg) for 2 weeks starting at 5 weeks after naïve T cell transfer. The disease activity index (DAI) was checked daily, and histopathological score, macroscopic injury score, and colon length were evaluated upon sacrifice. Macrophages and T cells from the spleen were analyzed by flow cytometry. Gene expression in colon tissue was measured by qRT-PCR and cytokine profiles in plasma was measured by cytometric bead array. Myeloperoxidase (MPO) activity was measured using the MPO activity kit.

Results

Oral administration of LMT503 ameliorated adoptive T cell transfer-induced colitis in mice. The DAI, histopathological score, and macroscopic injury score were significantly decreased after the administration of LMT503 in a dose-dependent manner. The LMT503-treated group showed significantly increased mucin production in the colon. Th1, Th17 cells, and M1 macrophages in the spleen were suppressed, and M2 macrophages were induced by the administration of LMT503. MPO activity and gene expressions of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in colon tissue were suppressed by the administration of LMT503. And the level of inflammatory cytokines, such as IL-2, TNF-α, and IFN-γ, in plasma were significantly suppressed by the administration of LMT503. Especially, LMT503 treatment significantly increased the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a), a master regulator of mitochondrial biogenesis, suggesting that LMT503 modulates cellular metabolism towards an anti-inflammatory metabolism.

Conclusion

Our data suggest that the anti-inflammatory effect of LMT503 ameliorates murine adoptive T cell transfer-induced colitis by modulating cellular metabolism and immune cell modulation. Therefore, LMT503 may be a novel therapeutic drug that opens new avenues for the treatment of IBD.

References

1. Erben U, Loddenkemper C, Doerfel K, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7(8):4557-4576.
2. Ostanin DV, Bao J, Koboziev I, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G135-G146.
3. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234-4243.
4. Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med. 2019;11(502):eaaw1736.
5. Kiesler P, Fuss IJ, Strober W. Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol. 2015;1(2):154-170.

Introduction

Pediatric Acute Liver Failure (PALF) presents a considerable threat to children with a high risk of mortality, despite its rarity. However, the exact cause remains unknown in about half of the cases, emphasizing the need for continued investigation and advancements in our understanding of the condition. Recurrent Acute Liver Failure (RALF) represents an even more uncommon phenomenon, defying diagnosis despite thorough examination. The advent of Whole Exome Sequencing offers hope in uncovering its elusive genetic origins, potentially shedding light on specific genetic disorders underlying this condition.

Aims & Methods

This study aimed to report spectrum of Recurrent Acute Liver Failure (RALF) cases and role of Whole Exome Sequencing (WES) in establishing a cause for RALF, during January 2023 – January 2024 in a tertiary care institute.

Results

We report 4 cases of Recurrent Acute Liver Failure (RALF). First case was a 5 year old 1^st born female child of 3^rd degree consanguineous marriage who presented with RALF during febrile episodes at 10 months, 18 months and 5 years. Child had low GGT (19 IU/L) cholestasis initially. Etiological workup for Wilson, infective, metabolic was normal. Provisionally, Fever Associated Infantile Liver Failure (ILFS) was thought. But, Upper GI endoscopy revealed esophageal varices confirming portal hypertension, and liver biopsy revealed- acute on chronic hepatitis with cirrhosis, confirming chronic liver disease, which was in contrast to complete liver function resolution seen in ILFS. Change in gait and expressive language ability was lost from 3 years of age. The child had rigidity, increased deep tendon reflexes, tremor and ataxia on examination. Genetic analysis revealed homozygous (autosomal recessive) likely pathogenic variant of SCYL1 gene mutation leading to Spinocerebellar Ataxia 21.
The second child also presented with RALF at 8 months, 1year and 1.5 years during febrile episodes, with low GGT Cholestasis. WES revealed pathogenic variant of SCYL1 gene mutation leading to Spinocerebellar Ataxia 21. Child died at 1.5years of age.
Third child is a 10 year old girl presented with multiple fever-related RALF since 9 years of age and was asymptomatic in between episodes. As the cause was indeterminate after extensive evaluation, WES was done which revealed novel compound heterozygote mutation in RINT1 gene in exon 8 and 12.
The fourth child is a sibling of third case who succumbed with the first acute liver failure following a febrile episode at 12 years of age.

Conclusion

Understanding the genetic basis of PALF is crucial for accurate diagnosis and management. Genetic testing, including targeted gene sequencing or whole-exome sequencing, can help identify these mutations and provide insights into the underlying causes of PALF in affected individuals. This information is essential for personalized treatment approaches and genetic counseling for families. In addition to metabolic and mitochondrial diseases, mutations in genes related to both cytosolic and mitochondrial pathways—such as NBAS, TRMU, IRAS, MARS, RINT1, and SCYL1—have been implicated in pediatric acute liver failure (PALF).

References

1. Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R, Berutti R, Adam R, Aldrian D, Baric I, Baumann U. Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology. 2024 May 1;79(5):1075-87.
2. Çakır M, İssi F, Güven B, Yakici N, Karaguzel G, Selimoglu A. Rare Causes of Recurrent Acute Liver Failure In Children: Infantile Liver Failure Syndromes. Klinische Pädiatrie. 2023 Jul;235(04):245-9.
3. Youssef, Mariam et al. “CALFAN (Low γ-Glutamyl Transpeptidase (GGT) Cholestasis, Acute Liver Failure, and Neurodegeneration) Syndrome: A Case Report with 3-Year Follow-Up after Liver Transplantation in Early Adulthood.” Case reports in hepatology vol. 2023 3010131. 31 Jul. 2023, doi:10.1155/2023/3010131