Gastroenterology and Hepatology from Bed to Bench

Acute and chronic failure in liver function may give rise to cognitive and non-cognitive impairments in the brain, namely hepatic encephalopathy (HE). Liver diseases may cause cholestasis, which is defined as the impaired secretion of bile. It is characterized by the accumulation of substances in plasma that are normally excreted in bile such as bile acids. Cholestasis can lead to hepatic encephalopathy. Several investigations have indicated that HE induces several symptoms, such as the impairment of learning and memory, anxiolytic-like behaviors, alterations in sleep pattern, and tremors. It has been reported that after HE, all classical neurotransmitter systems such as opioidergic, dopaminergic, cholinergic, GABAergic, adrenergic, serotonergic, and glutamatergic systems can be altered. This review focuses on cholestasis, hepatic encephalopathy, and behavioral disorders.

Keywords: Acute liver failure, Cognitive impairments, Neurotransmitter systems.

(Please cite as: Eslimi Esfahani D, Zarrindast MR. Cholestasis and behavioral disorders. Gastroenterol Hepatol Bed Bench 2021;14(2):95-107).

Aim: The aim of this study was to evaluate the expression of MALAT1 and the relationship between its expression with clinical characteristics in an Iranian gastric cancer patient.

Background: Long non-coding RNAs (LncRNAs) play critical roles in the initiation and development of gastric cancer. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved lncRNA and plays key roles in various types of human cancer. However, our understanding of the role of lncRNAs in the occurrence and development of gastric cancer is not fully clear.

Methods: This cross-sectional study was performed on 41 gastric tumor tissue samples with matched normal adjacent tumor tissues. The RNA level of lncRNA MALAT1 gene was assessed using quantitative Real-time polymerase chain reaction. B2M was used as an internal control. The 2 ^-ΔΔCq method was adopted to determine expression fold changes.

Results A significant association was observed between the levels of MALAT1 in gastric tumor tissues compared with normal adjacent tissues (mean= 1.558, p= 0.014). In addition, clinicopathologic data on MALAT1 RNA expression levels in gastric cancer tissues was evaluated. No significant association was observed between the relative expression of MALAT1 and the stage, grade, H. pylori infection, and tumor size groups among gastric cancer patients (p= 0.82, p= 0.904, p= 0.407, and p= 0.701, respectively).

Conclusion: The current results showed that MALAT1 has a significant association in gastric cancer. The expression of MALAT1 may be used as a diagnostic biomarker for monitoring gastric cancer patients.

Keywords: Gastric cancer, MALAT1, Lncrna, Clinicopathologic feature.

(Please cite as: Chaleshi V, Asadzadeh Aghdaei H, Nourian M, Iravani SH, Jalaeikhoo H, Rajaeinejad H, et al. Association of MALAT1 expression in gastric carcinoma and the significance of its clinicopathologic features in an Iranian patient. Gastroenterol Hepatol Bed Bench 2021;14(2):108-114).

Aim: The aim of this study was to apply the Bayesian mixture cure rate frailty model to determine the factors that influence short-term and long-term survival of patients with gastric cancer

Background: Determining the risk factors of gastric cancer is currently considered very important, because the disease has become one of the most dangerous types of mortal cancers. Therefore, it is possible to determine the effective risk factors of short-term and long-term survival in patients through utilizing this model.

Methods: The present retrospective study was conducted on 339 gastric cancer patients whose data was recorded in hospitals of Kerman province, Iran, during 2001-2015. In the study, the Bayesian mixture cure rate frailty model was used to determine the effective factors of short-term and long-term survival in patients.

Results: In the present study, the event of interest occurred for 57.5% of patients. Over time, the survival rate of cancer patients reached its lowest point, approximately 0.3 at the end of study. According to the results of the present study, variables of chemotherapy (β=-0.35 (-0.75, -0.03) and OR=1.59 (1.08, 2.19)), morphology (β =-0.98(-1.45, -0.48) and OR=2.99 (1.78, 4.17)), and metastasis (β =0.42(0.10, 0.93) and OR=0.39(0.01, 0.84)) were identified as effective factors in short-term and long-term survival of patients.  

Conclusion: The effective factors of long-term and short-term survival can be identified by utilizing the Bayesian mixture cure rate frailty model, while it is impossible through conventional models of survival analysis. Chemotherapy, morphology, and metastasis are the most important effective factors of short-term and long-term survival in patients with gastric cancer.

Keywords: Gastric cancer, Short-term survival, Long-term survival, Cure rate frailty model, Bayesian inference.

(Please cite as: Karamoozian A, Baneshi MR, Bahrampour A. Short-term and long-term survival of patients with gastric cancer. Gastroenterol Hepatol Bed Bench 2021;14(2):115-122).

Aim: Efforts to explore biomarkers and biological pathways involved in the disease are needed to improve colorectal cancer (CRC) diagnosis and alternative treatments

Background: The fourth common malignancy in the world is colorectal cancer. The over-all burden is predicted to rise by 2030.

Methods: In the current study, nine genes were selected. Previously, a panel of genes by Agendia, a classifier of robust gene expression (ColoPrint), was determined to significantly improve the prognostic accuracy of pathologic factors in stage II and III colorectal cancer patients. Five genes, including Ppara, Mctp1, Pyroxd1, Il2r, and Cyfip2, from this panel and four other genes which were not in this panel but were cited abundantly in the literature were selected. Then, expression levels of the selected genes in CRC tissue were compared with levels in adjacent normal tissue. To identify the pathways involved in CRC, gene set enrichment analysis was subsequently performed. Furthermore, to illustrate the relationship between genes in this disease, the cross-shaped co-expression pattern and gene regulatory network were determined using computational methods.

Results: This research found that the pairs of genes: {IL2R, CYFIP2}, {FOXM1, PPARA}, {MCTP1, CTSC}, and {PYROXD1, CYF1P2} are functionally related. Furthermore, two differentially expressed gene pairs ({FOXM1, PPARA} and {IL2R, CYFIP2}) are involved in the vascular endothelial growth factor receptor signaling pathway and the purine ribonucleoside diphosphate metabolic process, respectively.

Conclusion: This research found that the combination of computational analysis and laboratory data provided the opportunity to better characterize the relation between central colorectal cancer genes as well as possible pathways involved in the colorectal cancer.

Keywords: Colorectal cancer, Computational analysis, Real-time RT-PCR, Gene set enrichment analysis (GSEA), Gene regulatory network (GRN).

(Please cite as: Shabani S, Khayer N, Motalebzade J, Majidi zadeh T, Mahjoubi F. Characterization of pathways involved in colorectal cancer using real-time RT-PCR gene expression data. Gastroenterol Hepatol Bed Bench 2021;14(2):123-131).

Aim: To understand the mutual interaction of gastric motility and autonomic functions, the present study evaluated the association of heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) with gastric motility assessed by electrogastrography (EGG) at rest and during CPT and explored the effect of sympathetic activation by cold pressor test (CPT) on gastric motility.

Background: The autonomic nervous system has a significant influence on gastrointestinal motility. HRV is commonly employed to assess the functions of the autonomic nervous system. BPV and BRS are relatively newer techniques and give a more holistic picture of autonomic functions along with the short-term regulation of blood pressure (BP).

Methods: In fourteen young, healthy subjects, gastric motility was assessed by EGG. Beat-to-beat BP and lead II ECG were recorded to assess HRV, BPV, and BRS. BPV and BRS parameters were calculated for systolic, mean, and diastolic BP. Parameters of HRV and BPV were calculated for time and frequency domains. BRS was calculated by sequence and spectral methods.

Results Significant increases in diastolic BP (p = <0.0001) and EGG frequency (p = 0.0229) were observed during CPT. Significant correlations were observed between EGG frequencies and many of the HRV, BPV, and BRS parameters. The correlation coefficient was found to be highest between total power of HRV and EGG frequencies during baseline (p = 0.0107, r = -0.6571) and during CPT (p = 0.0059, r = -0.6935).

Conclusion: EGG frequency can be decreased by an acute increase in sympathetic activity induced by CPT. The novel findings are the significant correlations between many of the HRV, BPV, and BRS parameters and EGG frequency.

Keywords: Electrogastrography, Heart rate variability, Blood pressure, Baroreflex sensitivity, Autonomic nervous system.

(Please cite as: Prakash K, ThakurA, Malhotra AS. Association of heart rate variability, blood pressure variability, and baroreflex sensitivity with gastric motility at rest and during cold pressor test. Gastroenterol Hepatol Bed Bench 2021;14(2):132-140).

Background: Identification of competing endogenous RNAs (ceRNAs), especially circRNAs, have become new hotspots in cancer researches. Although, their roles and underlying mechanisms in colorectal cancer (CRC) development remain mostly unknown. The aim of this study was to integrate both coding and non-coding available microarray data in development of CRC coupled with bioinformatics analyses to understand a more inclusive pathobiologic map regarding their molecular interactions and functions.

Methods: The microarray data were retrieved from the Gene Expression Omnibus (GEO) database and analyzed. Several bioinformatics tools and databases including CircInteractome, CSCD, miRTarbBase, TargetScan, miRmap, GEPIA, STRING, Enrichr, DAVID, and MCODE were applied for further elucidation. Principal component analysis (PCA) has seperatly run for four datasets. The dysregulated circRNA-miRNA-mRNA network in CRC was constructed by Cytoscape. In addition, co-expression and protein-protein interaction (PPI) networks were established based on differentially expressed (DE) protein coding genes in CRC.

Results: PCA discloses colorectal tumor and normal tissuses could be distinguished not only by mRNAs expression profile, but also by both circRNAs and miRNAs expression profiles. We identified 14 DE mRNAs (commonly between two datasets), 85 DE miRNAs and 36 DE circRNAs in CRC tissues compared with normal tissues. Taking their potential interactions into account, a circRNA-miRNA-mRNA network was constructed. Then, according to ceRNA hypothesis, the axes with expression in the desired direction were extracted. Our results disclosed some DE circRNAs with potential oncogenic (circ_0014879) or tumor suppressive (circ_0001666 and circ_0000977) effects. Finally, PPI network suggests pivotal roles for DOCK2 and PTPRC dysregulation in progression of CRC, possibly by facilitating of tumor escape from immune surveillance.

Conclusion: Current study proposes a novel regulatory network consisting of DE circRNAs, miRNAs and mRNAs in CRC development that in turn highlights the roles of DE circRNAs at the upstream of oncotranscriptomic cascade in CRC development, suggesting their potentiality to be utilized as both prognostic and therapeutic biomarker.

Aim: This study investigated the safety and efficacy of tenofovir disoproxil fumarate (TDF) compared with lamivudine (LAM) in the prevention of recurrent HBV infection after liver transplantation (LT).

Background: Although the recurrence of hepatitis B virus after liver transplantation (LT) is now very uncommon with both nucleoside and nucleotide analogs represented with lamivudine and tenofovir disoproxil fumarate, respectively, few studies have compared the two classes.

Methods: A total of 302 HBV-related post-transplant patients who received liver transplants from deceased donors were enrolled in this retrospective study from 2011 to 2015 in the Shiraz Organ Transplant Center, Iran. The demographic data, kidney function, recurrence, resistance rate, and acute rejections at 1-, 6-, and 12-month intervals and after 12 months were compared on TDF (n=209) and lamivudine (n=93) groups.

Results: During a median follow-up period of 42.9 months, mean creatinine level was not significantly different between the two groups. Hepatitis B virus recurrence rate as well as acute graft rejection episode had no statistical difference in either group over the study period.

Conclusion: Kidney function, creatinine level, disease recurrence, and acute graft rejection were comparable between tenofovir disoproxil fumarate and lamivudine in patients who received follow-up periods.  

Keywords: Hepatitis B, Liver transplantation, Therapeutics.

(Please cite as: Ejtehadi F, Pashaei MR, Shamsaeefar AR, Motazedian N, Sivandzadeh GR, Niknam R, et al. Tenofovir in the treatment of hepatitis B virus infection after liver transplantation, a single center large population study. Gastroenterol Hepatol Bed Bench 2021;14(2):154-159).

Aim: The current study aimed to investigate the risk factors, endoscopic findings, and treatments of upper gastrointestinal bezoars.

Background: Bezoars are compact masses formed by the accumulation of dietary fiber, undigested food, hair, or medications. The majority of bezoars are asymptomatic, but they may cause serious symptoms or even life-threatening events such as bleeding, obstruction, or perforation

Methods: This retrospective study was conducted in three gastroenterology clinics between January 2016 and December 2019. Bezoars were detected in 109 of 15,830 endoscopy records (0.68%).

Results A total of 103 patients (52.4% male) were enrolled in this study. Mean patient age was 60.5±11.3 years. The most frequent risk factors were history of gastric surgery (25.2%), diabetes mellitus (21.3%), hypothyroidism (15.5%), trichophagia (5.8%), and anxiety disorders (2.9%), respectively. The most common endoscopic findings were peptic ulcers (34.9%), erosive gastritis/duodenitis (12.6%), and reflux esophagitis (10.6%). While bezoars were most commonly observed in the stomach (84.4%), the majority of them were phytobezoars (92.2%). The mean number of endoscopic interventions for each patient was 1.5 (range, 1-4). Endoscopy was successful in removing bezoars in 85.4%.

Conclusion: The synergistic effect of multiple factors for a long time, such as gastrointestinal surgery, diabetes mellitus or psychiatric disorders, may lead to bezoar formation. These risk factors should be avoided or treated in order to prevent bezoar formation and subsequent life-threatening complications.

Keywords: Bezoar, Risk factors, Endoscopic intervention.

(Please cite as: Hemmasi GR, Zanganeh E, Hosseini SA, Alimadadi M, Ahmadi A, Hajiebrahimi SH, et al. Risk factors, endoscopic findings, and treatments in upper gastrointestinal bezoars: Multi-center experience in Iran. Gastroenterol Hepatol Bed Bench 2021;14(2):160-164).

Aim: This study was designed to investigate the prevalence of Clostridioides difficile, its toxin-producing genes, and antibiotic resistance patterns in diarrheal samples from hospitalized patients in Hamadan, Iran.

Background: Today, concerns over Clostridioides difficile infection (CDI) have significantly increased due to reduced susceptibility to antibiotics used for CDI treatment. Toxins produced by C. difficile strains are associated with disease severity and outcome.

Methods: In this cross-sectional study, a total of 130 diarrheal samples of patients admitted to different wards of three hospitals in Hamadan from November 2018 to September 2019 were collected. C. difficile isolates were identified by culture on CCFA and PCR (Polymerase chain reaction). The presence of toxin-encoding genes (tcdA and tcdB) and binary toxin genes (cdtA and cdtB) was analyzed by PCR. Resistance of the isolates to metronidazole, vancomycin and clindamycin antibiotics was determined using agar dilution method.

Results: Out of 130 diarrheal samples from hospitalized patients, 16 (12.3%) C. difficile isolates were obtained. PCR results were positive for two toxin-producing genes, tcdA and tcdB, in all (100%) C. difficile isolates, and the binary toxin genes cdtA and cdtB were detected in 6 (37.5%) and 8 (50%) isolates, respectively. The results of antibiotic susceptibility testing showed resistance to metronidazole, vancomycin, and clindamycin in 3 (18.7%), 3 (18.7%), and 2 (12.5%) isolates, respectively, and all isolates were resistant to rifampicin.

Conclusion: The results of this study showed toxigenic C. difficile with tcdA⁺/tcdB⁺ profile is a major cause of nosocomial diarrhea in Hamadan, and clinical laboratories should routinely perform C. difficile diagnostic testing on diarrheal specimens of hospitalized patients. Resistance to conventional antibiotic therapy against C. difficile should be considered as a warning to prevent irrational administration of antibiotics.

Keywords: Clostridioides difficile, TcdA, TcdB, Binary toxin, Antibiotic resistance.

(Please cite as: Shokoohizadeh L, Alvandi F, Yadegar A, Azimirad M, Hashemi SH, Alikhani MY. Frequency of toxin genes and antibiotic resistance pattern of Clostridioides difficile isolates in diarrheal samples among hospitalized patients in Hamadan, Iran. Gastroenterol Hepatol Bed Bench 2021;14(2):165-173).

The incidence of intestinal volvulus as a cause of abdominal pain is rare in adults and normally presents during infancy. Approximately 90% of patients with volvulus are diagnosed within the first year of life, 80% of whom are diagnosed within the first month of life. The current case was a 34-year-old pregnant woman who was admitted to the hospital due to self-limited episodes of epigastric pain from a young age. The patient complained that the pains had recently worsened. Further clinical investigation led us to invasive intervention due to signs of obstruction, and the patient was transferred to the operating room. The case represents a rare incidence of intestinal volvulus in an adult and its complications through pregnancy.

Keywords: intestinal volvulus, abdominal pain, duodenal obstruction, intestinal obstruction.

(Please cite as: Talebzadeh H, Andalib SH, Andalib MM. Congenital intestinal volvulus with episodes of pain for long period of time: case report. Gastroenterol Hepatol Bed Bench 2021;14(2):174-177).

Dysphagia is a symptom with a broad differential diagnosis. Usually, the etiology of dysphagia is benign, but it is essential to rule out serious causes. It is also critical to think outside the box when the etiology is not obvious. Herein, we describe a case of multiple myeloma that initially presented with dysphagia.

An 81-year-old male patient presented with dysphagia to solid food associated with anorexia and weight loss of 22 kg over the last 6 months. The patient looked chronically ill and cachectic. Upper endoscopy showed patchy erythema in the gastric antrum. Gastric biopsy was consistent with gastric amyloidosis. Although serum and urine protein electrophoresis did not show a monoclonal (M) band, immunofixation did show elevated free kappa light chains and elevated free Kappa/Lambda ratio. Bone marrow biopsy was consistent with multiple myeloma. Although gastrointestinal involvement is common in amyloidosis, it is unusual for amyloidosis to initially present in the gastrointestinal tract. Identification and treatment of the underlying condition, e.g., multiple myeloma, can lead to regression of gastrointestinal amyloidosis.

Keywords: Multiple myeloma, Plasma cell disorders, Malignancy, Amyloidosis, Dysphagia.

(Please cite as: Ghazaleh S, Hindupur A, Nehme C, Khader Y, Ghanim M, Sheikh T, Alhmoud T. Gastric amyloidosis in a patient with dysphagia. Gastroenterol Hepatol Bed Bench 2021;14(2):178-180).

Herein we describe a rare case of a 59-year-old male who was diagnosed with giant hyperplastic polyps after referring with symptoms of abdominal pain and vomiting, and associated red-flag symptoms of unintentional weight loss and early satiety.

Keywords: Hyperplastic polyp, Gastric polyp, Gastric lesion, Gastroscopy.

(Please cite as: Dalkie N, Lane A, Lockett B, Rostami K. Symptomatic giant gastric hyperplastic polyp: a case report. Gastroenterol Hepatol Bed Bench 2021;14(2):181-184).

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin lymphoma (NHL). The gastrointestinal tract is the most involved extra-nodal site of NHL. Primary duodenal FL (DFL) is a rare entity with only a few reported cases. It mainly involves the second part of the duodenum and has an excellent prognosis. We report the case of a 74-year-old man who underwent esophagogastroduodenoscopy. Endoscopic findings revealed multiple small whitish mucosal nodules which were detected around the major duodenal papilla. Biopsy of these lesions was compatible with grade I FL. Further investigation failed to demonstrate any evidence of nodal or systemic involvement; thus, the clinical staging was stage I, according to the Lugano staging system. A “watch and wait” policy was chosen. Neither lesion aggregation nor lymphadenopathy was noted during the 5-year follow-up period. In conclusion, this was an uncommon case of DFL with an indolent nature and excellent prognosis. However, further studies are needed to clarify the characteristics, prognosis, and therapeutic approach.

Keywords: Follicular lymphoma, Duodenum, Lymph node, Non-Hodgkin lymphoma.

(Please cite as: Charoenlap C, Akarapatima K, Suwanno K, Rattanasupar A, Chang A. Primary follicular lymphoma of the duodenum: a case report and review of literatures. Gastroenterol Hepatol Bed Bench 2021;14(2):185-189).

(Please cite as: Zanganeh E, Hosseini SA, Alimadadi M, Seyyedmajidi MR. A 61-year-old man from Iran with intermittent obstruction of colon. Gastroenterol Hepatol Bed Bench 2021;14(2):190-192).

To The Editor

  [1] I read with great interest the very interesting review article by Osman et al who addressed the issue of neurological manifestations of coeliac disease (CD), with particular emphasis on gluten ataxia and immunological injury (1).

They have reviewed in detail the most relevant studies addressing the relationship of CD with cerebellar ataxia (CA) and immunopathology of enteric CD in comparison to neuronal pathology. The role of gluten-free diet (GFD) with special emphasis on its effect on improving symptoms of ataxia was also reviewed.

This topic is of great relevance since neurological manifestations can occur in about 10% of CD patients with CA, peripheral neuropathy, seizures, headache, cognitive impartment and various neuropsychiatrist disorders representing potentially extraintestinal manifestations of CD, as properly stated by the authors.

Although I consider this review to be of significant interest and very up-to-date, I feel that some issues would have deserved more emphasis owing to their clinical relevance.

In particular, when the Author discussed the potential spectrum of neurological manifestations occurring in CD patients, they omitted to mention multiple sclerosis, multifocal leukoencephalopathy, chorea, and attention/memory impairment, all of which are well known to be other neurological disorders potentially associated to CD (2).

Of major interest, I would also like to point out that among the autoantibodies potentially detectable in CD patients with neurological manifestations, other than anti-ganglioside antibodies, it is worth mentioning also anti-neuronal antibodies to central/enteric nervous systems detected by indirect immunofluorescence as previously reported (3-5).

These antibodies can be considered markers of neurological manifestations as they have been reported in more than 60% of CD patients with neurological manifestations and therefore should be included in the immunological assessment of CD patients due to their major clinical significance.

Received: 24 June 2020   Accepted: 29 August 2020

Reprint or Correspondence: Markus Wilhelmi, MD Medical Clinic I, Gastroenterology and Hepatology, Nutritional Medicine, University Hospital, Frankfurt, Germany.

E-mail: dr.markus.wilhelmi@gmail.com

ORCID ID: 0000-0003-0121-0627