TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis.

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7 rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also did not mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis.

Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

Chronic pancreatitis: Do serum biomarkers provide an association with an inflammageing phenotype?

BACKGROUND: Chronic pancreatitis is an inflammatory disorder of the pancreas that is associated with accelerated mortality for patients suffering from this disease. The association between chronic inflammation and accelerated biological ageing has been well described and is often referred to as "inflammageing". In this review we seek to determine how systemic inflammation in chronic pancreatitis may contribute to an accelerated ageing phenotype. METHODS: A systematic literature search with a predefined search protocol was performed on Medline, Embase and Cochrane libraries according to the PRISMA guidelines. RESULTS: The initial search identified 499 studies. After title, abstract and full text screen of the search results, 20 were included for further evaluation. In the 20 remaining articles 41 inflammatory mediators were identified - mainly involved in chronic inflammation, fibrosis and particularly cardinal features of inflammageing such as sarcopenia and osteoporosis. CONCLUSION: Chronic pancreatitis is associated with elevated levels of inflammatory mediators many of which are associated with an accelerated ageing phenotype and may explain some of the clinical sequelae of this disease.

Association of HFE gene C282Y and H63D mutations with liver cirrhosis in the Lithuanian population.

BACKGROUND AND OBJECTIVE: Liver cirrhosis is the end-stage disease of chronic liver injury. Due to differences in the natural course of chronic liver diseases, identification of genetic factors that influence individual outcomes is warranted. HFE-linked hereditary hemochromatosis (HH) predisposes disease progression to cirrhosis; however, the role of heterozygous C282Y or H63D mutations in the development of cirrhosis in the presence of other etiological factors is still debated. The aim of this study was to determine the association between heterozygous C282Y and H63D mutations and non-HH liver cirrhosis in Lithuanian population. MATERIALS AND METHODS: The patient cohort consisted of 209 individuals. Diagnosis of cirrhosis was confirmed by clinical, laboratory parameters, liver biopsy, and radiological imaging. Control samples were obtained from 1005 randomly selected unrelated healthy individuals. HFE gene mutations were determined using the PCR-RFLP method. RESULTS: The most common causes of cirrhosis were hepatitis C (33.9%), hepatitis B (13.6%), and alcohol (25.8%). C282Y allele was associated with the presence of cirrhosis (OR=2.07; P=0.005); this was also observed under recessive model for C282Y (OR=2.06, P=0.008). The prevalence of C282Y allele was higher in cirrhotic men than in controls (7.0% vs. 2.8%, P=0.002). The carriage of H63D risk allele (OR=1.54; P=0.02), heterozygous C282Y/wt and homozygous H63D/H63D genotypes were associated with liver cirrhosis in males (OR=2.48, P=0.008, and OR=4.13, P=0.005, respectively). CONCLUSIONS: Heterozygous C282Y mutation of the HFE gene was associated with liver cirrhosis in the Lithuanian population. In gender-related analysis, heterozygous C282Y and homozygous H63D mutations were linked to liver cirrhosis in men, not in women.

Sterile Fecal Filtrate From A Healthy Donor Improves Microbial Diversity In Patients With Hepatic Encephalopathy.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) remains one of the most debilitating complications of liver cirrhosis. Changes in gut microbiome composition have been linked to liver diseases and its complications including HE. Recent randomized controlled trials showed fecal microbiota transplantation to be safe and effective in HE treatment, however transferring unidentified live bacteria could cause various complications, including infections, especially in immunocompromised patients. This study aimed to evaluate the safety and efficacy of sterile fecal filtrate transfer (SFFT) for the modulation of the intestinal microbiome of patients with cirrhosis and HE. METHODS: A custom-made air pressure filtration device was used for the sterile fecal filtrate preparation. Seven patients received SFFT from the same healthy donor. Patients were monitored at least 30 days after the procedure. Cognition tests, blood and stool sampling were performed to assess the safety and efficacy of SFFT on HE, liver function, and stool microbiome composition on follow-up days 7 and 30. RESULTS: SFFT was well tolerated and resulted in fluctuations in the microbial composition of study participants: α-diversity increased in 4/7 of the patients, without robust engraftment of donors' microbial composition as assessed by ß-diversity analysis. No significant effect on cognition tests or liver function was noted after the procedure. One death occurred three months after the procedure, however, it was not related to the SFFT. CONCLUSIONS: Despite the effect on the gut microbiome, we did not observe robust improvement in patients' liver function or HE cognition tests after the procedure.

Circulating microbiome in patients with portal hypertension.

Portal hypertension (PH) in liver cirrhosis leads to increased gut permeability and the translocation of bacteria across the gut-liver axis. Microbial DNA has recently been detected in different blood compartments; however, this phenomenon has not been thoroughly analyzed in PH. This study aimed to explore circulating bacterial DNA signatures, inflammatory cytokines, and gut permeability markers in different blood compartments (peripheral and hepatic veins) of patients with cirrhosis and PH. The 16S rRNA blood microbiome profiles were determined in 58 patients with liver cirrhosis and 46 control patients. Taxonomic differences were analyzed in relation to PH, liver function, inflammatory cytokines, and gut permeability markers. Circulating plasma microbiome profiles in patients with cirrhosis were distinct from those of the controls and were characterized by enrichment of Comamonas, Cnuella, Dialister, Escherichia/Shigella, and Prevotella and the depletion of Bradyrhizobium, Curvibacter, Diaphorobacter, Pseudarcicella, and Pseudomonas. Comparison of peripheral and hepatic vein blood compartments of patients with cirrhosis did not reveal differentially abundant taxa. Enrichment of the genera Bacteroides, Escherichia/Shigella, and Prevotella was associated with severe PH (SPH) in both blood compartments; however, circulating microbiome profiles could not predict PH severity. Escherichia/Shigella and Prevotella abundance was correlated with IL-8 levels in the hepatic vein. In conclusion, we demonstrated a distinct circulating blood microbiome profile in patients with cirrhosis, showing that specific bacterial genera in blood are marginally associated with SPH, Model for End-Stage Liver Disease score, and inflammation biomarkers; however, circulating microbial composition failed to predict PH severity.

COVID-19 in a Patient with Liver Cirrhosis.

The outbreak of coronavirus disease 2019 (COVID-19) has recently become a serious issue affecting thousands of people worldwide. It is known that a substantial proportion of patients infected with COVID-19 have abnormal liver function tests; however, the consequences of this information is still not clear. Here we present the first case report of a patient with liver cirrhosis and COVID-19 in our centre. Resolution of COVID-19 symptoms was observed after six days of fever onset. We observed only slight fluctuations of liver enzymes, bilirubin levels and INR without clinical consequences in our case. We suggest testing for severe acute respiratory syndrome coronavirus on any cirrhotic patient on initial presentation, even without symptoms of COVID-19 in areas where the epidemic was prevalent.

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis.

BACKGROUND AND AIMS: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*S rs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13 (rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to test these associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. METHODS: The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stages I-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Adjusted p value of ≤ 0.016 was considered significant. RESULTS: Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium. SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkage disequilibrium with rs72613567; r 2 =0.96) also showed no overall association with liver disease, but the GG- genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associated with higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). CONCLUSIONS: We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis, while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis of different aetiology.

Systemic inflammation contributes to impairment of quality of life in chronic pancreatitis.

Chronic pancreatitis (CP) is a fibrotic disorder of the pancreas leading to clinical sequelae like pain and an excess of comorbidity including cardiovascular disease and cancers. The aim of this study was to determine the relationship between systemic inflammation and quality of life in patients with CP. Patients were prospectively recruited and underwent a quality of life assessment (EORTC QLQ-C30 and PAN 28). The serum inflammatory profile was assessed using an MSD 30-plex array. The relationship between clinical variables, inflammatory cytokines and quality of life was determined by a GLM-MANOVA and the individual impact of significant variables evaluated by a second ANOVA. In total, 211 patients with a median age of 53 years were recruited across 5 European centres. Gender, age, nicotine and alcohol abuse were clinical variables associated with altered quality of life. Systemic inflammation with high levels of pro-inflammatory cytokines (Eotaxin, IL-1ß, IL-7, IL-8, IL-12/IL-23p40, IL-12p70, IL-13, IL-16, IP-10, MCP-1, MCP-4, MDC, MIP-1a, TARC, TNFß) was associated with diminished quality of life in general and specific domains including pain, physical and cognitive functioning. As conclusion, CP is associated with a systemic inflammatory response that has a negative impact on quality of life and accelerates aging.

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population.

BACKGROUND AND AIMS: Genome-wide association studies have revealed an association between the risk of developing liver fibrosis or cirrhosis and the single nucleotide polymorphisms (SNPs) of the PNPLA3, RNF7, MERTK and PCSK7 genes. We aimed to validate these results in an Eastern European population. METHODS: We evaluated the associations between the PNPLA3 (rs738409), RNF7 (rs16851720), MERTK (rs4374383) and PCSK7 (rs236918) variants and liver fibrosis and cirrhosis in a series of consecutive patients recruited at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, during the period 2012-2015. The study included 317 individuals with liver cirrhosis, 154 individuals with liver fibrosis, and 498 controls. The studied SNPs were determined using RT-PCR TaqMan assays. RESULTS: MERTK and PCSK7 SNPs were not associated with liver fibrosis or cirrhosis. The PNPLA3 SNP rs738409 was associated with a higher risk of developing liver fibrosis (aOR: 1.65, P=0.001) and cirrhosis (aOR: 1.92, P=5.57*10-7). PNPLA3 genotypes were also associated with higher risk of developing liver fibrosis and cirrhosis in dominant (aOR: 1.98, P=2.20*10-5; aOR: 1.67, P=0.008, respectively) and recessive (aOR: 3.94, P=5.16*10-5; aOR: 3.02, P=0.003, respectively) models. RNF7 rs16851720 was associated with liver cirrhosis comparing CC vs. AA + CA genotypes (aOR: 0.26, P=0.020). CONCLUSION: Our study showed that PNPLA3 rs738409 and RNF7 rs16851720 confer an increased risk of developing liver fibrosis and cirrhosis in this Eastern European population, while the MERTK and PCSK7 SNPs are not associated with these conditions.