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Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: A proof of concept study

Published on Nov 9, 2019in Metabolism-clinical and Experimental6.513
· DOI :10.1016/j.metabol.2019.154005
Nikolaos Perakakis9
Estimated H-index: 9
(BIDMC: Beth Israel Deaconess Medical Center),
Stergios A. Polyzos32
Estimated H-index: 32
(A.U.Th.: Aristotle University of Thessaloniki)
+ 4 AuthorsChristos S. Mantzoros106
Estimated H-index: 106
(BIDMC: Beth Israel Deaconess Medical Center)
Abstract
Abstract Background Non-alcoholic fatty liver disease (NAFLD) affects 25–30% of the general population and is characterized by the presence of non-alcoholic fatty liver (NAFL) that can progress to non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis leading to hepatocellular carcinoma. To date, liver biopsy is the gold standard for the diagnosis of NASH and for staging liver fibrosis. This study aimed to train models for the non-invasive diagnosis of NASH and liver fibrosis based on measurements of lipids, glycans and biochemical parameters in peripheral blood and with the use of different machine learning methods. Methods We performed a lipidomic, glycomic and free fatty acid analysis in serum samples of 49 healthy subjects and 31 patients with biopsy-proven NAFLD (15 with NAFL and 16 with NASH). The data from the above measurements combined with measurements of 4 hormonal parameters were analyzed with two different platforms and five different machine learning tools. Results 365 lipids, 61 glycans and 23 fatty acids were identified with mass-spectrometry and liquid chromatography. Robust differences in the concentrations of specific lipid species were observed between healthy, NAFL and NASH subjects. One-vs-Rest (OvR) support vector machine (SVM) models with recursive feature elimination (RFE) including 29 lipids or combining lipids with glycans and/or hormones (20 or 10 variables total) could differentiate with very high accuracy (up to 90%) between the three conditions. In an exploratory analysis, a model consisting of 10 lipid species could robustly discriminate between the presence of liver fibrosis or not (98% accuracy). Conclusion We propose novel models utilizing lipids, hormones and glycans that can diagnose with high accuracy the presence of NASH, NAFL or healthy status. Additionally, we report a combination of lipids that can diagnose the presence of liver fibrosis. Both models should be further trained prospectively and validated in large independent cohorts.
  • References (36)
  • Citations (3)
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References36
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#1Stergios A. Polyzos (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 32
#2Nikolaos Perakakis (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 9
Last. Christos S. Mantzoros (Harvard University)H-Index: 106
view all 3 authors...
Abstract Lipodystrophy is a group of clinically heterogeneous, inherited or acquired, disorders characterized by complete or partial absence of subcutaneous adipose tissue that may occur simultaneously with the pathological, ectopic, accumulation of fat in other regions of the body, including the liver. Fatty liver adds significantly to hepatic and extra-hepatic morbidity in patients with lipodystrophy. Lipodystrophy is strongly associated with severe insulin resistance and related comorbidities...
3 CitationsSource
#1José M. MatoH-Index: 60
#2Cristina AlonsoH-Index: 10
Last. Shelly C. LuH-Index: 59
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3 CitationsSource
#1Laurent Castera (French Institute of Health and Medical Research)H-Index: 48
#2Mireen Friedrich-Rust (Goethe University Frankfurt)H-Index: 38
Last. Rohit Loomba (UCSD: University of California, San Diego)H-Index: 58
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Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sin...
23 CitationsSource
#1Stergios A. Polyzos (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 32
#2Jannis Kountouras (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 43
Last. Christos S. Mantzoros (VA Boston Healthcare System)H-Index: 106
view all 3 authors...
Abstract The obesity epidemic is closely associated with the rising prevalence and severity of nonalcoholic fatty liver disease (NAFLD): obesity has been linked not only with simple steatosis (SS), but also with advanced disease, i.e., nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis and hepatocellular carcinoma. As a consequence, apart from increasing all-cause mortality, obesity seems to increase liver-specific mortality in NAFLD patients. Given the lack of approved pharmacological ...
13 CitationsSource
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Last. Kay AhnH-Index: 14
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Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triacylglycerol (TAG) synthesis. Genetic knockdown or pharmacological inhibition of DGAT2 leads to a decrease in very-low-density lipoprotein TAG secretion and hepatic lipid levels in rodents, indicating DGAT2 may represent an attractive therapeutic target for treatment of hyperlipidemia and hepatic steatosis. We have previously described potent and selective imidazopyridine DGAT2 inhibitors with high oral bioavailability. Howe...
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#1Junfeng Ma (GUMC: Georgetown University Medical Center)H-Index: 2
#2Miloslav Sanda (Georgetown University)H-Index: 18
Last. Radoslav Goldman (Georgetown University)H-Index: 25
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Abstract Aberrant core fucosylation of proteins has been linked to liver diseases. In this study, we carried out multiple reaction monitoring (MRM) quantification of core fucosylated N-glycopeptides of serum proteins partially deglycosylated by a combination of endoglycosidases (endoF1, endoF2, and endoF3). To minimize variability associated with the preparatory steps, the analysis was performed without enrichment of glycopeptides or fractionation of serum besides the nanoRP chromatography. Spec...
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#1Giovanni Musso (UNITO: University of Turin)H-Index: 35
#2Maurizio Cassader (UNITO: University of Turin)H-Index: 46
Last. Roberto Gambino (UNITO: University of Turin)H-Index: 42
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The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid spec...
16 CitationsSource
#1Chrysoula Boutari (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 2
#2Nikolaos Perakakis (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 9
Last. Christos S. Mantzoros (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 106
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Abstract Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease and important unmet medical need. Current guidelines recommend, under specific restrictions, pioglitazone or vitamin E in patients with NASH and significant fibrosis, but the use of both remains off-label. We summarize evidence on medications for the treatment of nonalcoholic steatohepatitis (NASH), since NASH has been mainly associated with higher morbidity and mortality. Some of these medications are currently in p...
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#1Chrysoula Boutari (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 6
#2Christos S. Mantzoros (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 106
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In recent years, there has been a plethora of attempts to discover biomarkers that are more reliable than α-fetoprotein for the early prediction and prognosis of hepatocellular carcinoma (HCC). Efforts have involved such fields as genomics, transcriptomics, epigenetics, microRNA, exosomes, proteomics, glycoproteomics, and metabolomics. HCC arises against a background of inflammation, steatosis, and cirrhosis, due mainly to hepatic insults caused by alcohol abuse, hepatitis B and C virus infectio...
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