Gastroenterology and Hepatology from Bed to Bench

Non-alcoholic fatty liver disease is one of the main liver diseases worldwide. The most common cause of death in patients with non-alcoholic fatty liver disease is cardiovascular disease. The relationship between these two conditions has been well established. Indeed, identical reasons may contribute to the development of cardiovascular disease and non-alcoholic fatty liver disease with lifestyle factors such as smoking, sedentariness, poor nutritional habits, and physical inactivity being major aspects. This review focuses on potential pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver. PubMed, EMBASE, Orphanet, MIDLINE, Google Scholar, and Cochrane Library were searched for articles published between 2006 and 2022. Relevant articles were selected using the following terms: “Non-alcoholic fatty liver disease,” “Сardiovascular diseases,” “Pathophysiological mechanisms.” The reference lists of all identified articles were searched for other relevant publications as well. The pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver remain largely speculative and may include systemic low-grade inflammation, atherogenic dyslipidemia, abnormal glucose metabolism and hepatic insulin resistance, endothelial dysfunction, gut dysbiosis, as well as the associated cardiac remodeling, which are influenced by interindividual genetic and epigenetic variations. It is clear that the identification of pathophysiological mechanisms underlying cardiovascular disorders in non-alcoholic fatty liver disease will make the selection of therapeutic measures more optimal and effective.

Portal hypertensive gastropathy (PHG) and gastric antral vascular ectasia (GAVE) are two distinct entities that are frequently mistaken with each other, because they present with similar manifestations. This issue may cause catastrophic outcomes, as each one of them has a unique pathophysiology, thereby making their management approaches completely different. There are clinical clues that help physicians distinguish these two. Direct vision via upper endoscopy is often mandatory to establish the diagnosis, and sometimes biopsy is required. In this review, we sought to discuss different aspects of both conditions and highlight clinical evidence that may help in identifying and managing the disease appropriately.

In recent decades, the number of cases developing drug-induced esophagitis (DIE) has reportedly been growing, which indicates the significance of detecting medicines capable of causing this adverse reaction. This study aims to provide an updated review on recent case reports of DIE, to evaluate the possible mechanism of this side effect, and to provide helpful management. Data was gathered through searches of three databases, namely PubMed, Medline, and Cochrane. Seven drug categories were evaluated: antibiotics, bisphosphonates, cardiovascular medicines, chemotherapeutic agents, non-steroidal anti-inflammatory drugs (NSAIDs), other medications, and supplements. According to the findings, retrosternal pain, heartburn, odynophagia, and dysphagia are typical symptoms of DIE, and in most cases, DIE is a self-limiting side effect which can be resolved by removing the causative agent and providing supportive therapy.

Aim: The current study aimed to investigate sequence variations in the C-terminus of latent membrane protein 1 (LMP1) in Epstein-Barr virus (EBV) isolates from Iranian patients with chronic gastritis or gastric cancer (GC).

Background: LMP1 is the essential viral oncoprotein that is a key element in the immortalization of B cells. It contains a small twenty-four amino acid cytoplasmic N-terminal region, six transmembrane segments, and a two hundred amino acid cytoplasmic C-terminal domain. Most LMP1-mediated signal transduction events are moderated by some functional parts of the cytoplasmic C-terminal domain.

Methods: Thirty-two EBV positive biopsy tissues were obtained from patients with gastric cancer and patients with chronic gastritis. The C-terminal nucleotide sequences of LMP1 were amplified using nested-PCR and analyzed by DNA sequencing.

Results Four to eight copies of the 11 repeat elements (codon 254–302) were observed in the carboxyl-terminal site of patients, but no relationship was found between the number of repeat sequences and disease status. The 30-bp deletion corresponding to codon 345–354 of the B95-8 strain was observed in 34% of isolates, and the remaining samples were non-deleted. In the gastric cancer group, a higher number of 33-bp repeats (≥5 repeats) was observed in 30-bp-deletion (100%) than in non-deleted (42%) isolates, and the difference was statistically significant. Analysis revealed that a gastritis isolate may be the result of recombination between Alaskan and China1 strains.

Conclusion: Overall, the current results showed no association between C-terminal sequence variations of LMP1 and malignant or non-malignant isolate origin.

Aim: The current study analyzed the miRNA microarray dataset (GSE66274) and gene expression microarray dataset (GSE38129) with similar samples to achieve a better understanding of miRNA-mRNA interactions.

Background: The most common form of esophageal cancer is esophageal squamous cell carcinoma (ESCC). While, miRNAs are well recognized as having a critical regulatory role in human cancer, their responsibilities and mechanisms of miRNA-mRNA in ESCC are unknown.  

Methods: Differentially expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) were identified using the LIMMA package in R. In total, 478 DEmRNA (224 upregulated and 254 downregulated) and 39 DEmiRNA (15 upregulated and 24 downregulated) were screened. The RNAInter database analyzed miRNA-mRNA interactions; then, the miRNA-mRNA network was visualized by Cytoscape software. ClusterProfiler packages were used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for DEmRNA as targets of DEmiRNAs.

Results: KEGG pathway analysis indicated that the p53 signaling pathway, ECM−receptor interaction, and AGE−RAGE signaling pathway were significant. Cellular response to amino acid stimulus, negative regulation of apoptotic signaling pathway, and endoderm formation were most prevalent in the biological process category. Additionally, the collagen−containing extracellular matrix, actomyosin complex collagen trimers, basement membrane, and extracellular matrix structural constituent were more enriched.

Conclusion: Overall, the present survey provides evidence that could support the prognosis of esophageal tumors in the future.

Aim: The present double-blinded placebo-controlled randomized clinical trial evaluated prophylactic use of acetylcysteine for the prevention of liver injury in patients with severe COVID-19 pneumonia under treatment with remdesivir.

Background: Liver injury is reportedly common in patients with severe COVID-19 pneumonia and can occur not only as a result of disease progression, but as an iatrogenic reaction to remdesivir.

Methods: A total of 83 adult patients with severe COVID-19 pneumonia were randomly assigned in parallel groups to receive either acetylcysteine or placebo. All the patients received standard care according to institutional protocols, including remdesivir for a total of five days. One gram acetylcysteine was administered intravenously every 12 hours for 42 patients, and 41 patients received the same volume of 0.9% sodium chloride as placebo (Trial Registration: www.irct.ir identifier, IRCT20210726051995N1).

Results: After 5 days, median aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in the acetylcysteine than in the placebo group. Of those who received the placebo, 30 (73.2%), 4 (9.7%), and 3 (7.3%) patients had serum AST levels elevated between 1-2.5, 2.5-5, and over 5 times the upper limit of normal (ULN), respectively; while in the acetylcysteine group, 33 (78.6%) and 0 patients had AST levels between 1-2.5 and over 2.5 times ULN, respectively (p-value=0.037). In the acetylcysteine group, 23 (54.8%), 1 (2.4%), and 1 (2.4%) patient had serum ALT levels elevated between 1-2.5, 2.5-5, and over 5 times ULN, respectively; in the placebo group, however, 24 (58.5%), 7 (17.1%), and 1 (2.4%) patient had serum ALT levels between 1-2.5, 2.5-5, and over 5 times ULN, respectively (p-value=0.073).

Conclusion: Intravenous administration of acetylcysteine significantly prevents liver transaminases elevation and liver injury in seriously ill COVID-19 patients treated with remdesivir.

Aim: The current study explored the crucial dysregulate proteins and biochemical pathways in gastric ulcer as its main aim.

Background: Gastric ulcer as an acid-related gastrointestinal disease is known as one of the most public gastrointestinal disorders.

Methods: A total of 100 proteins from STRING database were analyzed by Cytoscape and its applications to find the central proteins and the related biochemical pathways. Action map analysis was applied to explore regulatory relationships between the critical proteins.

Results: Network analysis and gene ontology revealed that IL6, ALB, TNF, INS, IL1B, IL10, TP53, CXCL8, and PTGS2 are the highlighted proteins related to gastric ulcer. Six clusters of biochemical pathways, namely “response to external stimulus,” “multicellular organismal process,” “regulation of biological quality,” “cellular response to stimulus,” “cellular response to chemical stimulus,” and “transport” were identified as the dysregulated pathway in patients.

Conclusion: Down-regulation of TP53 by IL2, PTGS2, and TNF seems to be a main process occurring in gastric ulcer patients. 

Aim: The current study is the first performed in Qom to determine the prevalence of adenovirus and co-infections with rotavirus in children aged <15 years with gastroenteritis symptoms.

Background: Gastroenteritis-associated viral infections are a cause of death among young children worldwide, especially in developing countries. The Adenovirus species F (40 and 41) are responsible for a range of acute diarrhea cases among infants and children.  

Methods: Over a period of 9 months, a total of 130 children suffering from intestinal problems who referred to the infectious ward of Children's Hospital were enrolled in the current study. After clinical examination and collection of demographic information, fecal samples were obtained from the patients. Viral genomes were extracted with a commercial kit and amplified and typed by adenovirus-specific PCR assay. Adenovirus-positive samples were also evaluated for co-infection with rotavirus.

Results: Patients had a mean±SD age of 2.66±2.72 years; 63.1% of patients were male and 36.9% were female. Adenovirus infection was identified in 23 cases (17.7%), 21 (91.0%) and 2 (9.0%) of which were type 41 and type 40, respectively. Fever was the most common clinical manifestation among adenovirus-positive patients. No significant difference was observed between adenovirus infection and clinical symptoms, seasonal pattern, or serum laboratory results. Co-infection was found in only 5 cases (21.7%).

Conclusion: This study was the first to demonstrate adenovirus infection with a relatively high prevalence among children, especially infants, in Qom. The findings further revealed co-infection with rotavirus, indicating a health problem in this region.

Aim: The current study aimed to remove aflatoxin from reconstituted milk by adding three probiotics, namely Saccharomyces boulardii, Lactobacillus casei, and Lactobacillus acidophilus.

Background: Aflatoxins are poisonous substances produced by certain kinds of fungi that are found naturally all over the world. They can contaminate food crops and pose a serious health threat to humans and livestock. Microbial detoxification is one method of eliminating aflatoxins, including aflatoxin M1.

Methods: For this purpose, about 109 and 107 cfu/ml of S. boulardii, L. casei, and L. acidophilus were inoculated into skim milk without aflatoxin M1. The samples were then spiked by aflatoxin M1 in concentrations of 0.5 and 0.75 ng/ml. The concentration of the aflatoxin residing in supernatant of milk samples after different storage times (30 and 90 minutes) and temperatures of 4 ℃ and 37 °C was measured by ELISA method, and the results were confirmed by HPLC.

 Results: The results showed that the highest amount of aflatoxin M1 removal was related to S. boulardii (96.88 ± 3.79c) with a microbial density concentration of 109 cfu/ml and toxin concentration of 0.75 ng/ml at 37 °C for 90 minutes and then to L. acidophilus (71.46 ± 3.79b) with a microbial density concentration of 107 cfu/ml and toxin concentration 0.75 ng/ml at 4 °C for 90 minutes. Furthermore, the maximum level of AFM1 binding to 107 cfu/ml of L. casei with average binding percentages of 64.31 ± 3/79c was 0.75 ng/ml at 37 °C for 90 minutes.

Conclusion: The results revealed the possibility of using S. boulardii in combination with the selected probiotics of L. casei and L. acidophilus in the detoxification of AFM1-contaminated milk.

Simultaneous occurrence of immune-based gastrointestinal diseases and autoimmune hepatitis, although not common, is of clinical importance. Some clinical and laboratory findings such as severe pruritus and elevated alkaline phosphatase raise suspicion of a biliary disease which overlaps autoimmune hepatitis. A strong clinical suspicion of overlap syndrome in a patient with autoimmune hepatitis prompts more diagnostic evaluations like MRCP, liver biopsy, and secondary laboratory tests. Patients who fall into the category of overlap syndrome proceed with timely monitoring of known complications including colorectal carcinomas, cholangiocarcinomas, and gallbladder cancers. It is strongly recommended that all simultaneous immune-based involvements be searched prior to labeling a patient as having pure autoimmune hepatitis.

The current study attempted to express all challenges about a case with overlap syndrome referred to the gastroenterology ward of Taleghani Hospital and to review the latest articles and related guidelines about the diagnosis, treatment, complications, and surveillance of the mentioned patient with autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and inflammatory bowel disease (IBD).

Herein, we report an extremely rare case of histopathologically proven neurofibromatosis of the liver. A 15-year-old male, a known case of type I neurofibromatosis (NF1), referred to our hospital with a complaint of right upper quadrant pain. He had a café-au-lait spot and positive family history of NF1 in his mother. Laboratory data was within normal limits, and computed tomography (CT) revealed a large predominantly less attenuated infiltrative liver mass along the porta hepatis with extension to both lobes of the liver. Magnetic resonance imaging showed a large hypo-signal mass in T1-weighted images and hypersignal lesion in T2-sequences with faint enhancement, periportal distribution, and encasing of major branches of the portal vein without evidence of narrowing and invasion. A CT-guided biopsy was taken from both liver lobe lesions, and pathological diagnosis of the biopsy specimens confirmed plexiform neurofibromas of the liver. According to the extensive intrahepatic extension and periportal infiltration, the mass was unrespectable. Radiologists need to be familiar with the typical imaging features of the uncommon hepatic neoplasms. If imaging findings are not typical or diagnostic, a further biopsy should be performed again.

We report a case of a 72-year-old man who was referred to our tertiary medical center for endoscopic ultrasound (EUS) evaluation for an incidental 2-cm mass in the tail of the pancreas seen on computed tomography (CT). On EUS, a 22 mm by 13 mm, well-defined hypoechoic mass was identified within the pancreatic tail, and a fine-needle biopsy was performed. Histopathology revealed benign pancreatic parenchyma and the presence of lymphocytes. A technetium-99m sulfur colloid scan was performed, which demonstrated uptake in the pancreatic tail lesion consistent with an intra-pancreatic splenule. This case demonstrates that a splenule or accessory splenic tissue should remain in the differential diagnosis of a pancreatic mass. An accurate diagnosis of pancreatic splenule can preclude surgical resection. 

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