Pancreatitis as a Main Consequence of APOC2-Related Hypertriglyceridemia: The Role of Nonsense and Frameshift Variants.

APOC2-related hypertriglyceridemia occurs due to biallelic variants of this gene. Here, genotype-phenotype architecture of all pathogenic APOC2 variants is investigated among heterozygous and homozygous individuals. Clinical heterogeneity of various types of the variants is also described, and pancreatitis in more than half of homozygotes carrying chain-termination variants is highlighted as well. For this study, patients were selected who had a plasma triglyceride level above 250 mg/dL. The coding and intronic regions of the APOC2 gene were amplified using the Sanger sequencing to investigate the presence of variants. The genotypes, lipid profiles, and detailed clinical features were documented for all APOC2-related patients and heterozygous individuals. Pathogenicity of the variants was predicted and categorized using available bioinformatics tools such as MutationTaster and PolyPhen-2 and ACMG criteria. MetaDome and Phyre2 were applied for structural and functional in silico analyses. 40% (12 out of 30) of APOC2 variants were chain-termination (nonsense and frameshift) variants. These types of variants were determined in 60.53% of patients. 55% of these patients showed pancreatitis followed by lipemia retinalis (29%), abdominal pain (24%), hepatosplenomegaly (24%), and xanthomas (18%). The mean age of onset was about 22 years old. In at least 50% of 38 homozygous individuals, the TG level was more than 2000 mg/dL. More than 25% of heterozygous individuals showed at least one symptom. Pancreatitis and a severe form of HTG were found in 5 and 2% of heterozygous individuals, respectively. The main clinical features of APOC2-related hypertriglyceridemia include pancreatitis, lipemia retinalis, abdominal pain, hepatosplenomegaly, and xanthomas. Nonsense and frameshift homozygous variants usually lead to a severe form of hypertriglyceridemia. Pancreatitis is one of the main consequences of these types of mutations; thus, it is important to consider this point when evaluating asymptomatic individuals. Heterozygous individuals may become symptomatic due to the role of unknown modifying agent including environmental genetic factors.

Predictive three-biomarker panel in peripheral blood mononuclear cells for detecting hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers and accounts for a significant proportion of cancer-associated deaths worldwide. This disease, marked by multifaceted etiology, often poses diagnostic challenges. Finding a reliable and non-invasive diagnostic method seems to be necessary. In this study, we analyzed the gene expression profiles of 20 HCC patients, 12 individuals with chronic hepatitis, and 15 healthy controls. Enrichment analysis revealed that platelet aggregation, secretory granule lumen, and G-protein-coupled purinergic nucleotide receptor activity were common biological processes, cellular components, and molecular function in HCC and chronic hepatitis B (CHB) compared to healthy controls, respectively. Furthermore, pathway analysis demonstrated that "estrogen response" was involved in the pathogenesis of HCC and CHB conditions, while, "apoptosis" and "coagulation" pathways were specific for HCC. Employing computational feature selection and logistic regression classification, we identified candidate genes pivotal for diagnostic panel development and evaluated the performance of these panels. Subsequent machine learning evaluations assessed these panels' performance in an independent cohort. Remarkably, a 3-marker panel, comprising RANSE2, TNF-α, and MAP3K7, demonstrated the best performance in qRT-PCR-validated experimental data, achieving 98.4% accuracy and an area under the curve of 1. Our findings highlight this panel's promising potential as a non-invasive approach not only for detecting HCC but also for distinguishing HCC from CHB patients.

Vitamin D status as a predictor for liver transplant outcomes.

It is well known that vitamin D plays a pivotal role in immune system modulation; however, its role in liver transplantation (LT) has not yet been well elucidated. This study aimed to assess the association between vitamin D status and LT outcomes. This retrospective cohort study was conducted on 335 registered cirrhotic patients with end-stage liver disease (ESLD) who underwent LT during 2019-2021 and had measurement of serum vitamin D before LT. The association of vitamin D levels before LT with the odds of acute cellular rejection (ACR) and risk mortality was assessed by applying logistic and cox regression, respectively. The mean MELD-Na and serum level of vitamin D were 20.39 ± 9.36 and 21.52 ± 15.28 ng/ml, respectively. In the final adjusted model, there was a significant association between vitamin D deficiency in the pre-transplant period and odds of ACR (odds ratio [OR] 2.69; 95% confidence interval [CI] 1.50-4.68). Although in the crude model, vitamin D deficiency in the pre-transplant period was significantly associated with an increased risk of mortality after two years of follow-up (Hazard ratio (HR) = 2.64, 95% CI 1.42-4.33), after adjustment for potential confounders, the association of vitamin D status and mortality became non-significant (HR = 1.46, 95% CI 0.71-3.00). The present study provides evidence that pre-transplant serum vitamin D levels may be a predictor for ACR in patients with cirrhosis undergoing LT.

The prevalence of latent/chronic infection in liver transplant candidates in Taleghani Hospital of Tehran, Iran, from 2020 until 2021.

Aim: The present study aimed to study the prevalence of various latent infections in pre-transplanted patients. Background: Due to chronic immunosuppressive therapy, patients receiving organ transplants are at risk for reactivation of various infections. Due to the complications in the course of diagnosing and treating the post-transplant infection, screening transplant recipients and donors is vital. Methods: This retrospective cohort study was performed between March 2020 and 2021. A total of 193 patients receiving a liver transplant in Taleghani Hospital, Tehran, Iran were enrolled. Results: One-hundred and three (53.4%) patients were men, with an average age of 48.4 ± 13.3 years. Among viruses, 177 (91.7%) patients had a positive IgG titer for CMV. Anti-EBV IgG was positive in 169 (87.6%) patients. One-hundred and seventy-five (90.7%) patients had a positive IgG titer for the VZV. One-hundred and sixty-six (86.0%) cases had positive IgG anti-HSV antibodies. According to our findings, none of the patients were infected with HIV, but 9 (4.7%) cases and 141 (73.1%) had positive anti-HCV and anti-HAV IgG antibodies, respectively. HBV surface (HBs) antigen was also reported positive in 17 (8.8%) patients, while the HBs antibody was positive in 29 (15.0%) patients. Conclusion: In our study, most of the patients had positive serology for latent viral infections such as CMV, EBV, VZV, and HSV, but the prevalence of latent tuberculosis and viral hepatitis was low among transplant candidates.

Retroperitoneal lymphangioma as the final diagnosis of a middle-aged woman with abdominal pain: a case report.

BACKGROUND: Lymphangiomas are lesions attributed to congenital malformations of the lymphatic system, or acquired chronic obstruction of the lymphatic network due to trauma, radiation, surgical manipulation, inflammation, or infection. Overall, lymaphangiomas are rare, and particularly, retroperitoneal lymphangiomas are far more uncommon per reported cases. CASE PRESENTATION: A 49-year-old Iranian woman presented with a progressive abdominal pain since approximately 1 month before admission. She was found to have a retroperitoneal lymphangioma after a precise radiological and surgical workup. CONCLUSION: Retroperitoneal lymphangiomas are rare lesions, sometimes indistinguishable from malignant lesions originating from pancreas and adjacent organs. Complete surgical removal and histologic evaluation of the lesion is the gold standard of treatment and diagnosis.

Quantitative analysis of Epstein-Barr virus DNA in plasma and stomach biopsies of patients with gastric cancer.

Epstein-Barr virus (EBV) associated gastric carcinoma (EBVaGC) is a subtype of gastric cancer with distinct histological and molecular features. The study aimed to assess the EBV DNA copy number and the prevalence of EBVaGC in gastric cancer samples taken from Iranian patients. The next aim was to assess whether the DNA and microRNAs EBV are present in plasma. EBV load was analyzed in 68 gastric cancer biopsies and compared with the results of EBV-encoded small RNA in situ hybridization (EBER-ISH) test in these patients. After the detection of 6 EBV miRNAs in gastric tissue by stem-loop RT-PCR, plasma samples were evaluated for the viral load and EBV miRNAs. Four gastric cancer cases were EBER -ISH positive (5.8%), with a significantly higher viral load than the remaining cases, 47,781 vs. 1909 copies/µg of tissue DNA. Here, was also found a significant difference in plasma EBV load between EBER-positive and EBER-negative cases. Although EBV miRNAs were detectable in all the EBER-positive tumors, the test did not detect any of these miRNAs among the plasma samples tested. Our data indicate that the prevalence of EBVaGC among Iranian patients with gastric cancer is lower than the global prevalence and although none of the EBV miRNAs were detected in plasma, evaluation of EBV microRNAs in tumor tissue, especially miR-BART7-3p, may constitute useful biomarkers for diagnosis of EBVaGC.

New insights into extracellular and intracellular redox status in COVID-19 patients.

BACKGROUND: The imbalance of redox homeostasis induces hyper-inflammation in viral infections. In this study, we explored the redox system signature in response to SARS-COV-2 infection and examined the status of these extracellular and intracellular signatures in COVID-19 patients. METHOD: The multi-level network was constructed using multi-level data of oxidative stress-related biological processes, protein-protein interactions, transcription factors, and co-expression coefficients obtained from GSE164805, which included gene expression profiles of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and healthy controls. Top genes were designated based on the degree and closeness centralities. The expression of high-ranked genes was evaluated in PBMCs and nasopharyngeal (NP) samples of 30 COVID-19 patients and 30 healthy controls. The intracellular levels of GSH and ROS/O2• - and extracellular oxidative stress markers were assayed in PBMCs and plasma samples by flow cytometry and ELISA. ELISA results were applied to construct a classification model using logistic regression to differentiate COVID-19 patients from healthy controls. RESULTS: CAT, NFE2L2, SOD1, SOD2 and CYBB were 5 top genes in the network analysis. The expression of these genes and intracellular levels of ROS/O2• - were increased in PBMCs of COVID-19 patients while the GSH level decreased. The expression of high-ranked genes was lower in NP samples of COVID-19 patients compared to control group. The activity of extracellular enzymes CAT and SOD, and the total oxidant status (TOS) level were increased in plasma samples of COVID-19 patients. Also, the 2-marker panel of CAT and TOS and 3-marker panel showed the best performance. CONCLUSION: SARS-COV-2 disrupts the redox equilibrium in immune cells and the upper respiratory tract, leading to exacerbated inflammation and increased replication and entrance of SARS-COV-2 into host cells. Furthermore, utilizing markers of oxidative stress as a complementary validation to discriminate COVID-19 from healthy controls, seems promising.

Immunosuppressive regimens on conversion of cytomegalovirus infection to disease in liver transplant recipients.

Background: Cytomegalovirus (CMV) disease is one of the most common infectious complications after liver transplantation. It is the cause of numerous morbidity and mortalities. Intensity of immunosuppression defined as overall immunosuppressive drug dosage seems to affect infectious complications. The main purpose of this study is to investigate the intensity of immunosuppression on conversion of CMV infection to disease in this population. Methods: In this cross-sectional study, we retrospectively evaluated and analyzed the data of all recipients who underwent orthotopic liver transplantation (OLT) between March 2014 and March 2016 and had positive serum PCR for CMV after transplantation in follow- up course. Of 134 recipients, only 66 adult liver transplant recipients were eligible to be studied. Multiple variables such as MELD score, cold ischemic time, warm ischemic time, operative data, immunosuppressive drugs and regimen, plasma CMV viral load, donor and recipient CMV IgG serostatus were recorded and analyzed. Results: of the 66 patients, 50 (76%) had CMV infection and 16 (24%) had disease. There was significant association between donor CMV IgG serostatus, extra corticosteroid pulse therapy, acute cellular rejection, serum tacrolimus level and conversion of CMV infection to CMV disease (P=0.005, 0.001, 0.031, 0.031). Conclusion: It seems that the intensity of immunosuppression has influence on conversion rate of CMV infection to disease in liver recipients.

Passenger Lymphocyte Syndrome as a rare cause of hemolysis in a patient after small intestine transplantation, A case report and review of the literature.

Passenger lymphocyte syndrome (PLS) is a well-described phenomenon causing immune hemolytic anemia, mostly in non-ABO identical transplantations. The syndrome occurs when donor lymphocytes produce antibodies against the recipient's red blood cells. Although the syndrome is usually self-limited, further management with blood transfusions, immunosuppression, or plasmapheresis might be needed. A 23-year-old female with AB+ blood group underwent small intestine transplantation from a deceased donor with O+ blood group. She received rituximab, thymoglobin, and methylprednisolone as immunosuppressive induction. In the 9th postoperation day, she developed hemolysis which was primarily managed with blood transfusions and finally ceased by plasmapheresis and intravenous immunoglobulin. Few cases of PLS have been previously described in intestinal transplantation recipients. Correct diagnosis and management prevents severe hemolysis outcomes. Previous cases have been successfully treated with a combination of immune suppression, plasma exchange, and transfusions.

Long delay in diagnosis of a case with MEN1 due to concomitant presence of AIMAH with insulinoma: a case report and literature review.

BACKGROUND: ACTH-independent macronodular hyperplasia (AIMAH) is an uncommon disorder characterized by massive enlargement of both adrenal glands and hypersecretion of cortisol. Concomitant AIMAH and multiple endocrine neoplasia type1 (MEN1) is rare to our knowledge. CASE PRESENTATION: Herein, we describe a 32 year old woman with long history of prolactinoma and secondary ammonhrea presented with not-severe manifestation of hypoglycemia due to concomitant presence of insulinoma with AIMAH leading to 12 years delay of MEN1 diagnosis. Laboratory tests showed severe hypoglycemia associated with hyper insulinemia (non-fasting blood sugar = 43 mg/dl, insulin = 80.6 µIU /ml, C-peptide = 9.3 ng/ml) hyperparathyroidism (calcium = 10.3 mg/dl, phosphor = 3.1 mg/dl, PTH = 280 pg/ml) and chemical evidence of an ACTH-independent hypercortisolism (serum cortisol value of 3.5, after 1 mg dexamethasone suppression test serum ACTH value of 17 pg/ml, and high urinary cortisol level). Abdominal CT scan demonstrated two enhancing well-defined masses 27*20 mm and 37*30 mm in the tail and body of the pancreas, respectively, and a 36*15 mm mass in left adrenal gland (seven Hounsfield units). Dynamic pituitary MRI revealed a partial empty sella. The physical examination of the patient was unremarkable. Distal pancreatectomy and a left adrenalectomy were performed. After the surgery, we observed clinical and biochemical remission of hyper insulinemia and gradual decrease in urinary cortisol. The histological features of the removed left adrenal gland were consistent with AIMAH. Histological examination of the pancreatic lesions revealed well differentiated neuroendocrine tumors. Genetic abnormalities in the MEN1, heterozygote for pathogenic variant chr11; 645,773,330-64577333AGAC, c.249-252delGTCT, p. (11e85Serfs Ter33) in exon 2 were found. It was recommended the patient undergoes parathyroidectomy as soon as possible. CONCLUSION: Given the history and presentation of our case, we recommend that the clinicians consider the possibility of autonomous cortisol production in MEN1 patients who do not show severe symptoms of hypoglycemia in the presence of insulinoma.

Continuous Renal Replacement Therapy with Low Dose Systemic Heparin in Liver Transplant Recipients.

INTRODUCTION: Continuous renal replacement therapy (CRRT) is an effective dialysis method in critically ill patients. Citrate and heparin are commonly used as anticoagulants to prevent premature circuit clotting. The aim of this study was to evaluate the safety and efficacy of using low dose systemic heparin while on CRRT in liver transplant recipients. METHODS: We retrospectively evaluated and analyzed data from 29 liver transplant recipients undergoing CRRT in the postoperative course in this cross-sectional study. Numerous variables were recorded, such as coagulation parameters, duration of intensive care unit (ICU) stay, duration of dialysis, heparin dose, circuit life span, and anticoagulant complications. RESULTS: Out of 29 recipients, there were 16 (55%) female and 13 (45%) male. All participants underwent whole organ liver transplantation with a median age of 45 years. Overall, 98 successful dialysis sessions were recorded in this study with a mean circuit life span of 36 hours. Mean ± SD duration of CRRT for each recipient was 4.8 ± 3.1 days. The median total dose of heparin used for each recipient was 25,000 units , and the median dose of heparin per-day for each recipient was about 3,300 units. There were no episodes of anticoagulant-related bleeding complications. Thirteen (13.2%) episodes of premature circuit clotting occurred. We found a significant association between the first dose and total dose of heparin usage with first postoperative INR and PTT level (P < .05, P < .05, P < .001, and P < .05). CONCLUSION: In liver transplant recipients, low dose heparin during CRRT for patency of circuit is well tolerated.

A Case Series of Variable Manifestations of COVID-19 in Liver Transplant Recipients.

Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) that is known as COVID-19 is a new emerging respiratory infection attributed to novel coronavirus, firstly introduced in Wuhan, China, at the end of 2019. This infection is still of great concern because of various presentations of the disease, which are not fully understood. The manifestations of this virus among liver transplanted patients would be more challenging in the setting of immunosuppression. The focus of this study is to introduce different presentations of this virus in five liver transplant recipients referred to the gastroenterology ward of Taleghani Hospital, a teaching referral hospital in Tehran, Iran. These patients were started on different types of therapies for coronavirus infection, from only supportive care up to remdisivir infusion and hemoperfusion based on the severity of the disease. Additionally, they were advised to continue all their immunosuppressant agents with adjustment except for CellCept that was withheld.