Biomolecular map of albumin identifies signatures of severity and early mortality in acute liver failure

白蛋白 内科学 肉碱 医学 组学 胃肠病学 血脂异常 肝硬化 血清白蛋白 队列 生物化学 内分泌学 生物 生物信息学 疾病
作者
Neha Sharma,Sushmita Pandey,Manisha Yadav,Babu Mathew,Vasundhra Bindal,Nupur Sharma,Gaurav Tripathi,Sadam H. Bhat,Abhishak Gupta,Rakhi Maiwall,Shvetank Sharma,Shiv Kumar Sarin,Jaswinder Singh Maras
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:79 (3): 677-691 被引量:5
标识
DOI:10.1016/j.jhep.2023.04.018
摘要

•Albumin is hyperoxidised and hyperglycated and shows reduced (60%) binding capacity in ALF. •Albumin biomolecular composition (bound multi-omics profile) is severely deranged and correlates with severity in ALF. •Albumin biomolecular integration highlights hyperinflammation and mitochondrial failure linked to non-survival in ALF. •Albumin-bound metabolome showed the highest diagnostic accuracy for the prediction of early mortality in ALF. Background & Aims Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. Methods Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n = 40; survivors, n = 8; non-survivors, n = 32; and HC, n = 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n = 160; survivors, n = 53; non-survivors, n = 107; and HC, n = 20). Results In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria, Clostridium, etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l-acetyl carnitine, l-carnitine, pregnenolone sulfate, and N-(3-hydroxybutanoyl)-l-homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95–1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. Conclusions In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct ‘albuminome’ signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation. Impacts and Implications Here, we report that the biomolecular map of albumin is distinct and linked to severity and outcome in patients with acute liver failure (ALF). Detailed structural, functional, and albumin-omics analysis in patients with ALF led to the identification and classification of albumin-bound biomolecules, which could segregate patients with ALF predisposed to early mortality. More importantly, we found albumin-bound metabolites indicative of mitochondrial damage and hyperinflammation as a putative indicator of <30-day mortality in patients with ALF. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in patients with ALF. Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n = 40; survivors, n = 8; non-survivors, n = 32; and HC, n = 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n = 160; survivors, n = 53; non-survivors, n = 107; and HC, n = 20). In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria, Clostridium, etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l-acetyl carnitine, l-carnitine, pregnenolone sulfate, and N-(3-hydroxybutanoyl)-l-homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95–1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct ‘albuminome’ signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
量子星尘发布了新的文献求助10
1秒前
nightmare完成签到,获得积分20
2秒前
哭泣笑柳发布了新的文献求助10
3秒前
nightmare发布了新的文献求助10
5秒前
大橙子发布了新的文献求助10
8秒前
10秒前
Zhh完成签到 ,获得积分10
10秒前
Tina完成签到,获得积分10
12秒前
微生完成签到 ,获得积分10
12秒前
13秒前
chhzz完成签到 ,获得积分10
14秒前
飞舞伤寒发布了新的文献求助20
14秒前
曾珍发布了新的文献求助10
16秒前
qwe完成签到,获得积分10
17秒前
Xdz完成签到 ,获得积分10
17秒前
cai完成签到 ,获得积分10
20秒前
雨恋凡尘完成签到,获得积分0
23秒前
羊羔肉完成签到,获得积分10
25秒前
胖丁完成签到,获得积分10
25秒前
笨笨凡松完成签到,获得积分10
28秒前
飞舞伤寒完成签到,获得积分10
28秒前
贝利亚完成签到,获得积分10
30秒前
喜多多的小眼静完成签到 ,获得积分10
30秒前
30秒前
Dsunflower完成签到 ,获得积分10
31秒前
羊羔肉发布了新的文献求助50
32秒前
半夏发布了新的文献求助10
32秒前
33秒前
33秒前
大橙子发布了新的文献求助10
34秒前
星辰大海应助贝利亚采纳,获得10
34秒前
35秒前
sunny心晴完成签到 ,获得积分10
37秒前
独特的凝云完成签到 ,获得积分10
37秒前
TheDing完成签到,获得积分10
38秒前
传奇3应助lenetivy采纳,获得10
40秒前
积极的忆曼完成签到,获得积分10
41秒前
量子星尘发布了新的文献求助10
41秒前
酒剑仙完成签到,获得积分10
41秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038201
求助须知:如何正确求助?哪些是违规求助? 3575940
关于积分的说明 11373987
捐赠科研通 3305747
什么是DOI,文献DOI怎么找? 1819274
邀请新用户注册赠送积分活动 892662
科研通“疑难数据库(出版商)”最低求助积分说明 815022