scholarly journals A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women

2020 ◽  
Author(s):  
Alec T McIntosh ◽  
Renhuizi Wei ◽  
Jaeil Ahn ◽  
Brad E Aouizerat ◽  
Seble G Kassaye ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Pharmacological Intervention ◽  
Genetic Associations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hiv Coinfection ◽  
Liver Disease Progression ◽  
Increased Risk ◽  
Genomic Variant

HIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women's Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression.

scholarly journals A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247277
Author(s):  
Alec T. McIntosh ◽  
Renhuizi Wei ◽  
Jaeil Ahn ◽  
Brad E. Aouizerat ◽  
Seble G. Kassaye ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Pharmacological Intervention ◽  
Genetic Associations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hiv Coinfection ◽  
Liver Disease Progression ◽  
Increased Risk ◽  
Genomic Variant

HIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women’s Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression.

scholarly journals SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis

2019 ◽  
Vol 28 (3) ◽  
pp. 297-302 ◽  
Author(s):  
Viktorija Basyte-Bacevice ◽  
Jurgita Skieceviciene ◽  
Irena Valantiene ◽  
Jolanta Sumskiene ◽  
Vitalija Petrenkiene ◽  
...  
Keyword(s):  
Risk Factors ◽  
Liver Cirrhosis ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
P Value ◽  
Gene Variants ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Reduced Risk

Background & Aims: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*Srs17580) 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 testthese 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 stagesI-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelicdiscrimination 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 linkagedisequilibrium 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 associatedwith 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 ofdifferent aetiology.

scholarly journals Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nghiem Xuan Hoan ◽  
Pham Thi Minh Huyen ◽  
Mai Thanh Binh ◽  
Ngo Tat Trung ◽  
Dao Phuong Giang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Disease Progression ◽  
Infection Risk ◽  
Hbv Infection ◽  
Liver Disease Progression ◽  
Increased Risk ◽  
Programmed Cell Death 1

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

Early kidney dysfunction in non-alcoholic fatty liver disease - is transient elastography useful as a screening method?

2021 ◽  
Author(s):  
Marta Freitas ◽  
Vítor Macedo Silva ◽  
Sofia Xavier ◽  
Joana Magalhes ◽  
Carla Marinho ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Transient Elastography ◽  
Screening Method ◽  
Kidney Dysfunction ◽  
Alcoholic Fatty Liver ◽  
Increased Risk ◽  
Significant Liver Fibrosis

Introduction: Increasing evidence suggests an association between metabolic associated fatty liver disease (MAFLD) and chronic kidney disease (CKD). Timely prediction of early kidney dysfunction (EKD) is thus essential in this population, although a screening method is not stablished. We aimed to evaluate the role of transient elastography (TE) in predicting EKD in patients with MAFLD. Methods: Prospective cohort study that included patients with MAFLD scheduled for evaluation, between May/2019 and January/2020. Demographic, clinical and laboratory data, and TE parameters were obtained. EKD was defined as microalbuminuria (urinary albumin-to-creatinine ratio 30-300mg/g) and estimated glomerular filtration rate≥60mL/min/1.73m2. Significant liver fibrosis was defined as liver stiffness measurement (LSM)≥8.2kPa. Results: Included 45 patients with MALFD, 53.3% female gender, mean age of 53.5±10.9years. EKD was found in 17.8% of patients. MAFLD patients with EKD were significantly more obese (body mass index≥30) (75.0% vs 32.4%,p=0.045) and had significantly higher LSM (8.5±4.1 vs 5.8±2.2kPa,p=0.01). After adjustment of potential confounders for EKD the presence of liver fibrosis, remained a significant predictor of EKD, being associated with a 14.3-fold increased risk of EKD (p=0.04). The optimal cutoff value of LSM to predict EKD was 6.1kPa (sensitivity:85.7%; specificity:67.6%). Conclusion: Significant liver fibrosis is associated with a significant increased risk of EKD in patients with MAFLD, regardless of other comorbidities. Higher levels of LSM, particularly >6.1kPa, alert for timely identification of EKD and associated comorbidities, as well as their control, in order to prevent the development of CKD in the long term.

scholarly journals Increased liver stiffness in patients with severe sleep apnoea and metabolic comorbidities

2018 ◽  
Vol 51 (6) ◽  
pp. 1800601 ◽  
Author(s):  
Wojciech Trzepizur ◽  
Jérôme Boursier ◽  
Marc Le Vaillant ◽  
Pierre-Henri Ducluzeau ◽  
Séverine Dubois ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Liver Stiffness ◽  
Sleep Apnoea ◽  
Screening Tools ◽  
The Metabolic Syndrome ◽  
Obstructive Sleep ◽  
Increased Risk ◽  
Metabolic Comorbidities

The goal of this study was to assess the relationship between the severity of obstructive sleep apnoea (OSA) and liver stiffness measurement (LSM), one of the most accurate noninvasive screening tools for liver fibrosis in nonalcoholic fatty liver disease.The study included 147 patients with at least one criterion for the metabolic syndrome, assessed by polysomnography for suspected OSA. LSM was performed using transient elastography (FibroScan). Significant liver disease and advanced liver fibrosis were defined as LSM ≥7.3 and ≥9.6 kPa, respectively.23 patients were excluded because of unreliable LSM. Among 124 patients, 34 (27.4%) had mild OSA, 38 (30.6%) had moderate OSA and 52 (42.0%) had severe OSA. LSM values were 7.3– <9.6 kPa in 18 (14.5%) patients and ≥9.6 kPa in 15 (12.1%) patients. A dose–response relationship was observed between OSA severity and LSM values (p=0.004). After adjustment for age, sex, metabolic syndrome and insulin resistance, severe OSA was associated with an increased risk of LSM ≥7.3 kPa (OR 7.17, 95% CI 2.51–20.50) and LSM ≥9.6 kPa (OR 4.73, 95% CI 1.25–17.88).In patients with metabolic comorbidities, severe OSA is independently associated with increased liver stiffness, which may predispose to a higher risk of significant liver disease and poorer prognosis.

scholarly journals Association of TIMP1 Levels and Liver Disease Progression Among HIV/HCV Co-infected, HIV Mono-, HCV Mono-infected, and Healthy Groups from the MASH Cohort (FS09-07-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Hyojung Kim ◽  
Tan Li ◽  
Jacqueline Hernandez ◽  
Colby Teeman ◽  
Javier Tamargo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Disease Progression ◽  
Infected Group ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Funding Sources ◽  
Liver Disease Progression ◽  
Liver Fibrogenesis ◽  
Fibrosis Regression ◽  
Mean Differences

Abstract Objectives Antiretroviral therapy has increased life expectancy for HIV infected patients; however, this population is developing chronic illnesses associated with aging. Liver disease is a major cause of non-AIDS mortality, characterized by progressive fibrosis. Infection with HIV and with Hepatitis C Virus (HCV) promotes liver fibrogenesis. Tissue inhibitor of metalloproteinase-1 (TIMP1), inhibits fibrosis regression and is profibrogenic. Association between TIMP1 and liver disease progression in an aging population of HIV/HCV co-infected, HIV mono-infected, HCV mono-infected, and healthy groups from the Miami Adult Studies on HIV (MASH) cohort in Miami, Florida, was investigated. Methods Serum TIMP1 levels were determined by ELISA. A non-invasive estimate of liver fibrosis, FIB-4 score was calculated. Liver fibrosis was defined as FIB-4: Low <1.45, intermediate 1.45 < = FIB-4 < = 3.25, High >3.25. ANOVA with Tukey's test assessed the mean differences of FIB-4 score and TIMP1 level between groups, TIMP1 levels between 3 FIB-4 categories, and the effect of age on FIB-4 and TIMP1. Linear regression predicted the association of FIB-4 score and TIMP-1 level. Results Mean age of the cohort was 54.3 ± 8.1 years with no difference between groups. Mean FIB-4 for HIV/HCV co-infected group was the highest among the 4 groups (P < 0.05). Mean TIMP1 for HIV/HCV co-infected group was also the highest among the 4 groups (P < 0.05). FIB-4 and TIMP1 were associated and remained so (β = 0.01, SE = 0.002, P < 0.001) after adjusting for age. Mean TIMP1 for the high FIB-4 category was the highest among the 3 FIB-4 categories (P < 0.05). There was a direct effect of TIMP1 levels on FIB-4 category (P < 0.001). After adjusting for HIV/HCV co-infection (P < 0.001), HIV infection (P < 0.0001), HCV infection (P < 0.002), non-infection (P < 0.001) and age, the relationship between TIMP1 and FIB-4 remained significant. The adjusted TIMP1 mean for HIV/HCV co-infected group was significantly higher compared to HIV infected (P < 0.0001), HCV infected (P < 0.002), and healthy groups (P < 0.0001), regardless of age. Conclusions Age is a significant factor of liver diseases progression. Our findings of the highest levels of TIMP1 in HIV/HCV co-infected group, which had the highest liver fibrosis regardless of age, supports the role of TIMP1 as a regulator in the progression of hepatic fibrosis. Funding Sources National Institutes on Drug Abuse #5UO1DA040381.

scholarly journals Association of Toll-Like Receptor 3 Single-Nucleotide Polymorphisms and Hepatitis C Virus Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Mashael R. Al-Anazi ◽  
Sabine Matou-Nasri ◽  
Ayman A. Abdo ◽  
Faisal M. Sanai ◽  
Saad Alkahtani ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Hcv Infection ◽  
Nucleotide Polymorphisms ◽  
Toll Like Receptor ◽  
Single Nucleotide ◽  
Liver Disease Progression ◽  
Healthy Control ◽  
Arabian Population

Toll-like receptor 3 (TLR3) plays a key role in innate immunity by recognizing pathogenic, double-stranded RNAs. Thus, activation of TLR3 is a major factor in antiviral defense and tumor eradication. Although downregulation of TLR3 gene expression has been mainly reported in patients infected with hepatitis C virus (HCV), the influence of TLR3 genotype on the risk of HCV infection, HCV-related cirrhosis, and/or hepatocellular carcinoma (HCC) remains to be determined. Single-nucleotide polymorphisms (SNPs) within the TLR3 gene and their associations with HCV-related disease risk were investigated in a Saudi Arabian population in this study. Eight TLR3 SNPs were analyzed in 563 patients with HCV, which consisted of 437 patients with chronic HCV infections, 88 with HCV-induced liver cirrhosis, and 38 with HCC. A total of 599 healthy control subjects were recruited to the study. Among the eight TLR3 SNPs studied, the rs78726532 SNP was strongly associated with HCV infection when compared to that in healthy control subjects. The rs5743314 was also strongly associated with HCV-related liver disease progression (cirrhosis and HCC). In summary, these results indicate that distinct genetic variants of TLR3 SNPs are associated with HCV infection and HCV-mediated liver disease progression in the Saudi Arabian population.

scholarly journals Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mathieu Paquette ◽  
Ming Yan ◽  
Josué M. J. Ramírez-Reyes ◽  
Leeanna El-Houjeiri ◽  
Marco Biondini ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver ◽  
Disease Progression ◽  
Fatty Liver Disease ◽  
Whole Body ◽  
Alcoholic Fatty Liver ◽  
Hepatocellular Damage ◽  
Triglyceride Accumulation ◽  
Liver Disease Progression

AbstractNon-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.

scholarly journals CD4 Recovery on Antiretroviral Therapy Is Associated With Decreased Progression to Liver Disease Among Hepatitis C Virus-Infected Injecting Drug Users

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Jeffrey P. Anderson ◽  
C. Robert Horsburgh ◽  
Paige L. Williams ◽  
Eric J. Tchetgen Tchetgen ◽  
David Nunes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Antiretroviral Therapy ◽  
Disease Progression ◽  
Drug Users ◽  
Hiv Rna ◽  
Liver Disease Progression ◽  
Increased Risk ◽  
Immunodeficiency Virus

Abstract Background.  Human immunodeficiency virus (HIV) coinfection accelerates liver disease progression in individuals with chronic hepatitis C. We evaluated the associations of CD4, HIV RNA, and antiretroviral therapy (ART)-induced CD4 recovery with liver diagnoses in a prospective cohort of injecting drug users (IDUs). Methods.  We evaluated 383 coinfected IDUs in the Boston area, prospectively observed for a median of 1.8 years. Liver disease progression included the first occurrence of hepatocellular carcinoma, variceal bleeding, ascites, encephalopathy, or death due to hepatic failure. Multivariable-adjusted extended Cox models were specified to estimate hazard ratios (HRs) for comparisons of CD4, change in CD4 (from nadir), and HIV RNA with respect to liver disease progression events. Results.  Twenty-four persons experienced a liver disease progression event over 1155 person-years (2.1 per 100 person-years), including 20 deaths attributed to end-stage liver disease (1.7 per 100 person-years). CD4 at baseline and over follow-up strongly predicted liver disease progression (baseline CD4 &lt;200 vs ≥200: HR = 5.23, 95% confidence interval [CI], 2.30–11.92; time-updated CD4 &lt;200 vs ≥200: HR = 11.79, 95% CI, 4.47–31.07). Nadir CD4 was also a strong indicator (&lt;100 vs ≥100: HR = 3.52, 95% CI, 1.54–8.06). A lack of CD4 recovery (failure to increase 100 cells over nadir) among ART initiators was associated with increased risk (HR = 7.69; 95% CI, 2.60–22.69). Human immunodeficiency virus RNA was not significantly associated with liver disease progression. Conclusions.  Impaired immune function was highly predictive of liver disease progression in this cohort of IDUs, and a lack of CD4 recovery on ART was associated with increased risk of progression to HCV-associated liver disease.

Sign in / Sign up

Export Citation Format

Share Document