19 research outputs found
Transfemoral Osseointegration: Surgical and Patient Reported Outcomes for Lower Limb Reconstruction
Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study.
Background & aimsLittle is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort.MethodsWe performed a cross-sectional analysis of a cohort of well-characterized twins residing in Southern California including 60 pairs of twins (42 monozygotic and 18 dizygotic; average age, 45.7 ± 22.1 y; average body mass index, 26.4 ± 5.7 kg/m(2)). We collected data on medical history, physical examinations, fasting laboratory test results, and liver health; all participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver from January 2012 through January 2015. Hepatic steatosis was quantified noninvasively by MRI and determined based on the proton-density fat fraction (MRI-PDFF); liver fibrosis was measured based on stiffness measured by magnetic resonance elastography.ResultsTwenty-six of the 120 subjects (21.7%) had nonalcoholic fatty liver disease (defined as MRI-PDFF ≥ 5% after exclusion of other causes of hepatic steatosis). The presence of hepatic steatosis correlated between monozygotic twins (r(2) = 0.70; P < .0001) but not between dizygotic twins (r(2) = 0.36; P = .2). The level of liver fibrosis also correlated between monozygotic twins (r(2) = 0.48; P < .002) but not between dizygotic twins (r(2) = 0.12; P = .7). In multivariable models adjusted for age, sex, and ethnicity, the heritability of hepatic steatosis (based on MRI-PDFF) was 0.52 (95% confidence interval, 0.31-0.73; P < 1.1 × 10(-11)) and the heritability of hepatic fibrosis (based on liver stiffness) was 0.5 (95% confidence interval, 0.28-0.72; P <6.1 × 10(-11)).ConclusionsA study of twins provides evidence that hepatic steatosis and hepatic fibrosis are heritable traits
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Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study.
Background & aimsLittle is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort.MethodsWe performed a cross-sectional analysis of a cohort of well-characterized twins residing in Southern California including 60 pairs of twins (42 monozygotic and 18 dizygotic; average age, 45.7 ± 22.1 y; average body mass index, 26.4 ± 5.7 kg/m(2)). We collected data on medical history, physical examinations, fasting laboratory test results, and liver health; all participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver from January 2012 through January 2015. Hepatic steatosis was quantified noninvasively by MRI and determined based on the proton-density fat fraction (MRI-PDFF); liver fibrosis was measured based on stiffness measured by magnetic resonance elastography.ResultsTwenty-six of the 120 subjects (21.7%) had nonalcoholic fatty liver disease (defined as MRI-PDFF ≥ 5% after exclusion of other causes of hepatic steatosis). The presence of hepatic steatosis correlated between monozygotic twins (r(2) = 0.70; P < .0001) but not between dizygotic twins (r(2) = 0.36; P = .2). The level of liver fibrosis also correlated between monozygotic twins (r(2) = 0.48; P < .002) but not between dizygotic twins (r(2) = 0.12; P = .7). In multivariable models adjusted for age, sex, and ethnicity, the heritability of hepatic steatosis (based on MRI-PDFF) was 0.52 (95% confidence interval, 0.31-0.73; P < 1.1 × 10(-11)) and the heritability of hepatic fibrosis (based on liver stiffness) was 0.5 (95% confidence interval, 0.28-0.72; P <6.1 × 10(-11)).ConclusionsA study of twins provides evidence that hepatic steatosis and hepatic fibrosis are heritable traits
Scenario optimization modeling approach for design and management of biomass-to-biorefinery supply chain system
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Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study.
Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m2 , respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P < 0.0001).ConclusionsGenes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558)
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Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD.
Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG :0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG :0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018)
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Collagen Formation Assessed by N-Terminal Propeptide of Type 3 Procollagen Is a Heritable Trait and Is Associated With Liver Fibrosis Assessed by Magnetic Resonance Elastography.
N-terminal propeptide of type 3 procollagen (PRO-C3) is a biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). This study examines the association between PRO-C3 concentration and liver fibrosis assessed by magnetic resonance elastography (MRE)-measured stiffness (MRE-stiffness) and the heritability of PRO-C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross-sectional analysis of a well-characterized prospective cohort of 306 participants, including 44 probands with NAFLD-cirrhosis and their 72 first-degree relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first-degree relatives, and 72 controls without NAFLD and their 72 first-degree relatives. Liver steatosis was assessed by magnetic resonance imaging proton density fat fraction, and liver fibrosis was assessed by MRE-stiffness. Serum PRO-C3 was assessed by competitive, enzyme-linked immunosorbent assay. We assessed the familial correlation of PRO-C3 concentration, the shared gene effects between PRO-C3 concentration and liver steatosis and fibrosis, and the association between PRO-C3 concentration and genetic variants in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing (MBOAT), and glucokinase regulator (CGKR) genes. In multivariable-adjusted models including age, sex, body mass index, and ethnicity, serum PRO-C3 correlated strongly with liver fibrosis (r2 = 0.50, P < 0.001) and demonstrated robust heritability (h2 , 0.36; 95% confidence interval [CI], 0.07, 0.59; P = 0.016). PRO-C3 concentration and steatosis had a strong genetic correlation (shared genetic determination: 0.62; 95% CI, 0.236, 1.001; P = 0.002), whereas PRO-C3 concentration and fibrosis had a strong environmental correlation (shared environmental determination: 0.55; 95% CI, 0.317, 0.717; P < 0.001). PRO-C3 concentrations were higher in carriers of the TM6SF2 rs58542926-T allele compared with noncarriers: 15.7 (± 10.5) versus 10.8 (± 5.7) ng/L (P = 0.047). Conclusion: Serum PRO-C3 correlates with MRE-assessed fibrosis, is heritable, shares genetic correlation with liver steatosis and shares environmental correlation with liver fibrosis. PRO-C3 concentration appears to be linked to both fibrosis and steatosis and increased in carriers of the TM6SF2 rs58542926 risk allele
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Association Between Obesity and Discordance in Fibrosis Stage Determination by Magnetic Resonance vs Transient Elastography in Patients With Nonalcoholic Liver Disease.
Background & aimsMagnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques used to detect liver fibrosis in nonalcoholic fatty liver disease. MRE detects fibrosis more accurately than TE, but MRE is more expensive, and the concordance between MRE and TE have not been optimally assessed in obese patients. It is important to determine under which conditions TE and MRE produce the same readings, so that some patients can simply undergo TE evaluation to detect fibrosis. We aimed to assess the association between body mass index (BMI) and discordancy between MRE and TE findings, using liver biopsy as the reference, and validated our findings in a separate cohort.MethodsWe performed a cross-sectional study of 119 adults with nonalcoholic fatty liver disease who underwent MRE, TE with M and XL probe, and liver biopsy analysis from October 2011 through January 2017 (training cohort). MRE and TE results were considered to be concordant if they found patients to have the same stage fibrosis as liver biopsy analysis. We validated our findings in 75 adults with nonalcoholic fatty liver disease who underwent contemporaneous MRE, TE, and liver biopsy at a separate institution from March 2010 through May 2013. The primary outcome was rate of discordance between MRE and TE in determining stage of fibrosis (stage 2-4 vs 0-1). Secondary outcomes were the rate of discordance between MRE and TE in determining dichotomized stage of fibrosis (1-4 vs 0, 3-4 vs 0-2, and 4 vs 0-3).ResultsIn the training cohort, there was 43.7% discordance in findings from MRE versus TE. BMI associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.69; 95% confidence interval, 1.15-2.51; P = .008) after multivariable adjustment by age and sex. The findings were confirmed in the validation cohort: there was 45.3% discordance in findings from MRE versus TE. BMI again associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.52; 95% confidence interval, 1.04-2.21; P = .029) after multivariable adjustment by age and sex.ConclusionsWe identified and validated BMI as a factor significantly associated with discordance of findings from MRE versus TE in assessment of fibrosis stage. The degree of discordancy increases with BMI