Fundación Investigación Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain.
Am J Gastroenterol. 2011 Sep;106(9):1629-37. doi: 10.1038/ajg.2011.123. Epub 2011 Apr 12.
Between 30 and 50% of the cirrhotic patients who do not show symptoms of clinical hepatic encephalopathy (HE) present minimal hepatic encephalopathy (MHE), with mild cognitive impairment. MHE impairs the quality of life, increases the risk of suffering accidents, predicts the appearance of clinical HE, and is associated with shortened lifespan. Early detection of MHE would be very useful. The "gold standard" for MHE diagnosis is the psychometric hepatic encephalopathy score (PHES). However, it is time consuming and needs adjusting for age and educational level. It would be very useful to have some blood biomarker reflecting the presence of MHE in cirrhotic patients. The aim of this work was to identify serum molecules useful as biomarkers for MHE.
We measured in 63 controls, 43 cirrhotic patients without MHE, and 44 patients with MHE, from Hospital Clinico de Valencia, serum levels of different amino acids, cyclic guanosine monophosphate (cGMP), nitrites+nitrates, and 3-nitrotyrosine. We analyzed for each parameter its diagnostic accuracy as an indicator of MHE, as assessed using the PHES.
These studies supported that 3-nitro-tyrosine is a good marker for MHE. To validate its utility as a biomarker for MHE, we analyzed in a second cohort of 44 cirrhotic patients without MHE and 18 patients with MHE, from Hospital Arnau de Vilanova, serum levels of 3-nitro-tyrosine, methionine, and citrulline. Citrulline (173±17%), methionine (173±16%), and 3-nitro-tyrosine (857±92%) were increased in sera from patients with MHE when compared with those without MHE. The receiver operating characteristic (ROC) curve analysis of 3-nitro-tyrosine for the diagnosis of MHE in the first cohort showed an area under the curve (AUC) value of 0.96 (95% confidence interval 0.93-0.99). At the cutoff of 14 nM, the specificity was 93%, sensitivity 89%, and positive and negative predictive values were both 91%. When the same cutoff was applied to the second cohort, the specificity was 83% and sensitivity was 94%. The positive and negative predictive values were 70 and 97%, respectively.
This pilot study, to be validated in a larger cohort, shows that determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values.
在没有出现临床肝性脑病（HE）症状的肝硬化患者中，有 30%至 50%存在轻微肝性脑病（MHE），伴有轻度认知障碍。MHE 会降低生活质量，增加发生意外的风险，预测临床 HE 的出现，并与寿命缩短有关。早期发现 MHE 将非常有用。MHE 诊断的“金标准”是心理测量性肝性脑病评分（PHES）。但是，该方法耗时，需要根据年龄和教育水平进行调整。如果有一些反映肝硬化患者 MHE 存在的血清生物标志物将非常有用。本研究的目的是确定用于 MHE 的血清标志物。
我们测量了来自瓦伦西亚临床医院的 63 名对照者、43 名无 MHE 的肝硬化患者和 44 名 MHE 患者的血清中不同氨基酸、环鸟苷单磷酸（cGMP）、亚硝酸盐+硝酸盐和 3-硝基酪氨酸的水平。我们分析了每种参数作为 PHES 评估的 MHE 指标的诊断准确性。
这些研究表明，3-硝基酪氨酸是 MHE 的一个很好的标志物。为了验证其作为 MHE 生物标志物的效用，我们在来自阿瑙德维拉诺瓦医院的 44 名无 MHE 的肝硬化患者和 18 名 MHE 患者的第二组队列中分析了血清 3-硝基酪氨酸、蛋氨酸和瓜氨酸的水平。与无 MHE 的患者相比，MHE 患者的血清中 3-硝基酪氨酸（857±92%）、蛋氨酸（173±16%）和瓜氨酸（173±17%）升高。第一组患者的 3-硝基酪氨酸用于 MHE 诊断的受试者工作特征（ROC）曲线分析显示曲线下面积（AUC）值为 0.96（95%置信区间 0.93-0.99）。在 14 nM 的截断值下，特异性为 93%，灵敏度为 89%，阳性和阴性预测值均为 91%。当将相同的截断值应用于第二组时，特异性为 83%，灵敏度为 94%。阳性和阴性预测值分别为 70%和 97%。
这项初步研究，需要在更大的队列中进行验证，表明通过简单且不耗时的血清 3-硝基酪氨酸测定来识别 MHE 患者具有良好的灵敏度、特异性和阳性及阴性预测值。
