Journal of Hepatology ( IF 26.8 ) Pub Date : 2023-04-26 , DOI: 10.1016/j.jhep.2023.04.018 Neha Sharma 1 , Sushmita Pandey 1 , Manisha Yadav 1 , Babu Mathew 1 , Vasundhra Bindal 1 , Nupur Sharma 1 , Gaurav Tripathi 1 , Sadam H Bhat 1 , Abhishak Gupta 1 , Rakhi Maiwall 2 , Shvetank Sharma 1 , Shiv Kumar Sarin 2 , Jaswinder Singh Maras 1
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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.
中文翻译：
白蛋白的生物分子图谱确定了急性肝衰竭的严重程度和早期死亡率的特征
背景与目标
急性肝衰竭（ALF）与高死亡率相关。白蛋白结构和功能的改变已被证明与肝硬化的结果相关。我们对白蛋白进行了生物分子分析，以确定其与ALF 肝细胞损伤和早期死亡率的相关性。
方法
共有 225 名参与者（200 名 ALF 患者和 25 名健康对照 [HC]）入组。从训练队列的基线血浆中纯化白蛋白（ALF，n = 40；幸存者，n = 8；非幸存者，n = 32；HC，n = 5）；分析修改、功能和结合的多组学特征；并在测试队列中进行验证（ALF，n = 160；幸存者，n = 53；非幸存者，n = 107；HC，n = 20）。
结果
在 ALF 患者中，白蛋白比 HC 患者更加氧化和糖基化，具有独特的多组学特征，在非幸存者中更是如此 ( p <0.05)。在非幸存者中，白蛋白更常与炎症相关的蛋白质、晚期糖基化终产物、与精氨酸、脯氨酸代谢、胆汁酸和线粒体分解产物相关的代谢物结合（ p <0.05，错误发现率<0.01）。非幸存者中细菌分类群（李斯特菌、梭菌等）的增加与脂质（甘油三酯 [4:0/12:0/12:0] 和磷脂酰丝氨酸 [39:0]）和代谢物（胆色素原和烟酸）相关（r 2 >0.7)。基于多组学特征的非存活检测概率 >90%，并显示与白蛋白功能和临床参数直接相关 (r 2 >0.85)。基于前五种代谢物（即烟酸、L-乙酰肉碱、L-肉碱、孕烯醇酮硫酸盐和N- (3-羟基丁酰基)-L-高丝氨酸内酯）建立的代谢物检测概率显示诊断准确度为 98% （AUC 0.98，95% CI 0.95-1.0）并区分有早期死亡倾向的 ALF 患者（对数秩<0.05）。在测试队列 1（血浆和配对一滴血）中使用高分辨率质谱分析和五种机器学习算法进行验证时，代谢组组显示死亡率预测的准确度/灵敏度和特异性 >92%。
结论
在 ALF 中，白蛋白被过度氧化并且基本上功能失调。我们的研究概述了独特的“白蛋白组”特征，能够区分易于早期死亡或需要紧急肝移植的 ALF 患者。
影响和启示
在这里，我们报告白蛋白的生物分子图谱是独特的，并且与急性肝衰竭（ALF）患者的严重程度和结果相关。对 ALF 患者进行详细的结构、功能和白蛋白组学分析，对白蛋白结合生物分子进行了鉴定和分类，从而可以分离出易早期死亡的 ALF 患者。更重要的是，我们发现白蛋白结合代谢物表明线粒体损伤和过度炎症，这是 ALF 患者 <30 天死亡率的推定指标。这项临床前研究验证了白蛋白组分析对于了解 ALF 患者的病理生理学和不良预后指标的发展的效用。
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