Plasminogen Activator Inhibitor‐1 Predicts Quantity of Hepatic Steatosis Independent of Insulin Resistance and Body Weight

Holzberg, Jeffrey R.; Jin, Ran; Le, Ngoc‐Anh; Ziegler, Thomas R.; Brunt, Elizabeth M.; McClain, Craig J.; Konomi, Juna V.; Arteel, Gavin E.; Vos, Miriam B.

doi:10.1097/mpg.0000000000001096

Cited by 11 publications

(12 citation statements)

References 34 publications

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“…(31) PAI1 has also been reported as a predictor of NASH and NAFLD activity score in obese children (9) and as a predictor of steatosis severity in another cohort. (15) The investigators hypothesized that PAI1 might be involved in NASH hepatic inflammation; indeed tPAI1 retained significance as a predictor in multivariable modeling of lobular inflammation and aPAI1 of portal inflammation in our cohort.…”

Section: Discussionmentioning

confidence: 60%

“…Most studies did not evaluate NASH histology, instead relying on surrogate markers or imaging as a substitute for diagnosis . Plasminogen activator inhibitor 1 (PAI1) has been associated with NAFLD in three studies in children as well as adult studies; but other markers, including tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐6, IL‐10, and resistin have been inconsistent predictors of NAFLD in smaller cohorts of adults and children (n = 40‐65) …”

Section: Introductionmentioning

confidence: 99%

“…(6)(7)(8)(9)(10)(11)(12)(13)(14) Most studies did not evaluate NASH histology, instead relying on surrogate markers or imaging as a substitute for diagnosis. (8,(11)(12)(13)(14) Plasminogen activator inhibitor 1 (PAI1) has been associated with NAFLD in three studies in children (9,10,15) as well as adult studies; but other markers, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-6, IL-10, and resistin have been inconsistent predictors of NAFLD in smaller cohorts of adults and children (n 5 40-65). (7,9,10,(16)(17)(18) This study provides a unique examination of a set of plasma biomarkers in a large cohort of children with biopsy-proven NAFLD.…”

Section: Introductionmentioning

confidence: 99%

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Association between cytokines and liver histology in children with nonalcoholic fatty liver disease

Perito

Ajmera

Bass

et al. 2017

Hepatology Communications

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Background Reliable non-invasive markers to characterize inflammation, hepatocellular ballooning, and fibrosis in nonalcoholic fatty liver disease (NAFLD) are lacking. We investigated the relationship between plasma cytokine levels and features of NAFLD histology to gain insight into cellular pathways driving NASH and to identify potential non-invasive discriminators of NAFLD severity and pattern. Methods Cytokines were measured from plasma obtained at enrollment in pediatric participants in NASH Clinical Research Network studies with liver biopsy-proven NAFLD. Cytokines were chosen a priori as possible discriminators of NASH and its components. Minimization of Akaike Information Criterion (AIC) was used to determine cytokines retained in multivariable models. Results Of 235 subjects, 31% had “Definite NASH” on liver histology, 43% had “Borderline NASH”, and 25% had NAFLD but not NASH. Total plasminogen activator inhibitor 1 (PAI1) and activated PAI1 levels were higher in pediatric participants with Definite NASH and with lobular inflammation. Interleukin-8 (IL-8) was higher in those with stage 3–4 fibrosis and lobular inflammation. sIL-2rα was higher in children with stage 3–4 fibrosis and portal inflammation. In multivariable analysis, PAI1 variables were discriminators of Borderline/Definite NASH, definite NASH, lobular inflammation and ballooning. IL-8 increased with steatosis and fibrosis severity; sIL-2rα increased with fibrosis severity and portal inflammation. IL-7 decreased with portal inflammation and fibrosis severity. Conclusions Plasma cytokines associated with histology varied considerably among NASH features, suggesting promising avenues for investigation. Future, more targeted analysis is needed to identify the role of these markers in NAFLD and to evaluate their potential as non-invasive discriminators of disease severity.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association between cytokines and liver histology in children with nonalcoholic fatty liver disease

Perito

Ajmera

Bass

et al. 2017

Hepatology Communications

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“…Exclusion criteria were currently attempting weight gain or loss, cirrhosis, renal disease/insufficiency, recent acute illness in the past 4 weeks, or pregnancy. More details of the sample are described elsewhere . For most participants (n = 29), plasma samples from baseline were used for metabolomics analysis in this study.…”

Section: Methodsmentioning

confidence: 99%

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high‐resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography–mass spectrometry was performed on plasma samples from a combined cross‐sectional sample of children and adolescents ages 2‐25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole‐body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

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“…Evidence from animal studies indicate a potential role of PAI‐1 in the initiation of NAFLD and demonstrate that reducing PAI‐1 production significantly reverses hepatic steatosis and hepatic lipid accumulation . Our previous study in children showed that PAI‐1 was correlated with the quantity of hepatic steatosis, measured by magnetic resonance spectroscopy, independently of obesity and insulin resistance . However, in that study, as well as the other previous studies in children, no information on severity of inflammation or fibrosis was available, and no lipid markers for CVD risk were reported.…”

Section: Introductionmentioning

confidence: 77%

Association between plasminogen activator inhibitor‐1 and severity of liver injury and cardiovascular risk in children with non‐alcoholic fatty liver disease

Jin

Krasinskas

et al. 2016

Pediatric Obesity

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Plasminogen Activator Inhibitor‐1 Predicts Quantity of Hepatic Steatosis Independent of Insulin Resistance and Body Weight

Cited by 11 publications

References 34 publications

Association between cytokines and liver histology in children with nonalcoholic fatty liver disease

Association between cytokines and liver histology in children with nonalcoholic fatty liver disease

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics

Association between plasminogen activator inhibitor‐1 and severity of liver injury and cardiovascular risk in children with non‐alcoholic fatty liver disease

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