Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine

2019 ◽  
Author(s):  
Zhipeng Liu ◽  
Yang Zhang ◽  
Sarah Graham ◽  
Roger Pique-Regi ◽  
Xiaocheng Charlie Dong ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Total Cholesterol ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Central Obesity ◽  
Mendelian Randomization ◽  
Alcoholic Fatty Liver ◽  
A Genome ◽  
Increased Risk

ABSTRACTBackgroundNon-alcoholic fatty liver disease (NAFLD) is epidemiologically correlated with both type 2 diabetes (T2D) and obesity. However, the causal inter-relationships among the three diseases have not been completely investigated.AimWe aim to explore the causal relationships among the three diseases.Design and methodsWe performed a genome-wide association study (GWAS) on fatty liver disease in ∼400,000 UK BioBank samples. Using this data as well as the largest-to-date publicly available summary-level GWAS data, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis. This analysis tested the causal inter-relationship between NAFLD, T2D, and obesity, as well as the association between genetically driven NAFLD (with two well-established SNPs at the PNPLA3 and TM6SF2 loci) and glycemic and lipidemic traits, respectively. Transgenic mice expressing the human PNPLA3 I148I (TghPNPLA3-I148I) and PNPLA3 I148M (TghPNPLA3-I148M) isoforms were used to further validate the causal effects.ResultsWe found that genetically instrumented hepatic steatosis significantly increased the risk for T2D (OR=1.3, 95% CI: [1.2, 1.4],p=8.3e-14) but not the intermediate glycemic phenotypes at the Bonferroni-adjusted level of significance (p<0.002). There was a moderate, but significant causal association between genetically driven hepatic steatosis and decreased risk for BMI (β=- 0.027 SD, 95%CI: [−0.043, −0.01],p=1.3e-4), but an increased risk for WHRadjBMI (Waist-Hip Ratio adjusted for BMI) (β=0.039 SD, 95%CI: [0.023, 0.054],p=8.2e-7), as well as a decreased level for total cholesterol (β=-0.084 SD, 95%CI [−0.13, −0.036],p=6.8e-4), but not triglycerides (β=0.02 SD, 95%CI [−0.023, 0.062],p=0.36). The reverse MR analyses suggested that genetically driven T2D (OR=1.1, 95% CI: [1.0, 1.2],p=1.7e-3), BMI (OR=2.3, 95% CI: [2.0, 2.7],p=1.4e-25) and WHRadjBMI (OR=1.5, 95% CI: [1.3, 1.8],p=1.1e-6) causally increase the NAFLD risk. In the animal study, as compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed higher fasting glucose level and reduced glucose clearance. Meanwhile, the TghPNPLA3-I148M mice demonstrated a reduced body weight, increased central to peripheral fat ratio, decreased circulating total cholesterol as compared to the TghPNPLA3-I148I controls.ConclusionThis large-scale bidirectional MR study suggests that lifelong, genetically driven NAFLD is a causal risk factor for T2D (hence potentially a “NAFLD-driven T2D” subtype) and central obesity (or “NAFLD-driven obesity” subtype), but protects against overall obesity; while genetically driven T2D, obesity, and central obesity also causally increase the risk of NAFLD, hence a “metabolic NAFLD”. This causal relationship revealed new insights into disease subtypes and provided novel hypotheses for precision treatment or prevention for the three diseases.

scholarly journals Colonic Diverticulosis and Non-Alcoholic Fatty Liver Disease: Is There a Connection?

Medicina ◽  
2021 ◽  
Vol 58 (1) ◽  
pp. 38
Author(s):  
Ivana Pantic ◽  
Sofija Lugonja ◽  
Nina Rajovic ◽  
Igor Dumic ◽  
Tamara Milovanovic
Keyword(s):  
Blood Pressure ◽  
Liver Disease ◽  
Fatty Liver ◽  
Total Cholesterol ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Colonic Surgery ◽  
Colonic Diverticulosis ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Background and Objectives: The development and severity of colonic diverticulosis and non-alcoholic fatty liver disease (NAFLD) has been associated with several components of metabolic syndrome (MetS). Therefore, this study aimed to evaluate a possible connection between NAFLD, colonic diverticulosis, and MetS. Materials and Methods: This retrospective study included patients diagnosed with diverticulosis between January 2017 and December 2019. Data regarding the patient demographics, Diverticular Inflammation and Complication Assessment (DICA) score and category, disease localization, hepatic steatosis, blood pressure, comprehensive metabolic panel, need for colonic surgery, and co-morbidities were collected from medical records. Results: A total of 407 patients with a median age of 68 years (range, 34–89 years) were included (male: 53.81%). The majority was diagnosed with left-sided diverticulosis (n = 367, 90.17%) and an uncomplicated disease course (DICA category 1, n = 347, 85.3%). Concomitant hepatic steatosis was detected in 47.42% (n = 193) of patients. The systolic blood pressure, triglycerides, total cholesterol, C-reactive protein (CRP), and fasting glucose were higher in the NAFLD group (p < 0.001, p < 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively). A higher prevalence of hypertension (HTA), type 2 diabetes mellitus (T2DM), and hypothyroidism was noted in the same group of patients (p < 0.001, p < 0.001, and p = 0.008, respectively). High-density lipoprotein cholesterol was lower in patients with more severe forms of diverticulosis (DICA category 2 and 3), while CRP levels were significantly higher (p = 0.006 and p = 0.015, respectively). HTA and NAFLD were more common in patients with more severe forms of colonic diverticulosis (p = 0.016 and p = 0.025, respectively). Using a multivariate logistic regression, the DICA score, CRP, total cholesterol, HTA, and hypothyroidism were identified as discriminating factors for the presence of hepatic steatosis. Conclusion: Components of metabolic dysregulation were prominent in patients diagnosed with colonic diverticulosis and concomitant hepatic steatosis. HTA, T2DM, and hypothyroidism were more frequently observed in this group. Hepatic steatosis was more commonly detected in more severe forms of colonic diverticulosis.

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 Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome

2010 ◽  
Vol 69 (2) ◽  
pp. 211-220 ◽  
Author(s):  
J. Bernadette Moore
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Response To Treatment ◽  
Health Concern ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease in both adults and children worldwide. As a disease spectrum, NAFLD may progress from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. An estimated 20–35% of the general population has steatosis, 10% of whom will develop the more progressive non-alcoholic steatohepatitis associated with markedly increased risk of cardiovascular- and liver-related mortality. Development of NAFLD is strongly linked to components of the metabolic syndrome including obesity, insulin resistance, dyslipidaemia and type 2 diabetes. The recognition that NAFLD is an independent risk factor for CVD is a major public health concern. There is a great need for a sensitive non-invasive test for the early detection and assessment of the stage of NAFLD that could also be used to monitor response to treatment. The cellular and molecular aetiology of NAFLD is multi-factorial; genetic polymorphisms influencing NAFLD have been identified and nutrition is a modifiable environmental factor influencing NAFLD progression. Weight loss through diet and exercise is the primary recommendation in the clinical management of NAFLD. The application of systems biology to the identification of NAFLD biomarkers and factors involved in NAFLD progression is an area of promising research.

scholarly journals Correlation of Gut Firmicutes/Bacteroidetes Ratio with Fibrosis and Steatosis in Patients with Non-alcoholic Fatty Liver Disease

2020 ◽  
Author(s):  
Chyntia Olivia Maurine Jasirwan ◽  
Akhmadu Muradi ◽  
Irsan Hasan ◽  
Marcellus Simadibrata ◽  
Ikhwan Rinaldi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Central Obesity ◽  
Gastrointestinal Microbiota ◽  
Alcoholic Fatty Liver ◽  
Microbiota Diversity ◽  
Alcoholic Fatty Liver Disease ◽  
High Triglyceride

Abstract Background : We investigated the gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) and its correlation with fibrosis and steatosis as reflected in the controlled attenuation parameter and transient elastography valuesMethods : A cross-sectional study was performed on 37 patients with NAFLD at Cipto Mangunkusumo National General Hospital from December 2018 to March 2019. The gut microbiota was investigated in fecal samples with 16S RNA sequencing using the next-generation sequencing platform MiSeq (Illumina).Results : NAFLD was more common in patients with metabolic syndrome. Firmicutes, Bacteroidetes, and Proteobacteria were the predominant phyla. Bacteroides was more dominant than Prevotella, contrary to the results in previous studies on normal populations in Indonesia. Microbiota dysbiosis was observed in most samples. The gastrointestinal microbiota diversity was significantly decreased in patients with NAFLD with high triglyceride levels and central obesity. The Firmicutes/Bacteroidetes ratio correlated with steatosis and obesity, whereas some other species in the lower taxonomy were mostly correlated with steatosis and obesity without fibrosis. Proteobacteria is the only phylum strongly correlated with fibrosis in patients with normal body mass index.Conclusions : The gut microbiota diversity was decreased in patients with NAFLD with high triglyceride levels and central obesity, and certain gut microbes were correlated with fibrosis and steatosis.

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