3月份发表的一项初步研究显示，分析呼出气体中的挥发性有机化合物是一种能够准确诊断非酒精性脂肪性肝炎(NASH)的非侵入性检测方法。这种检测可减少不必要的肝活检和与评估血浆转氨酶水平相关的漏诊(J. Hepatol. 2013;58:543-8)。
在这项研究中，荷兰马斯特里赫特大学医学中心的Froukje J. Verdam博士及其同事采用气相色谱-质谱法评估了2007年10月~2011年5月间连续收治的65例超重或肥胖患者腹腔镜手术前采集的呼气样本，并将这些结果与术中采集的肝活检组织学分析结果以及血浆丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)水平评估结果进行比较。
总体而言，肝活检显示，39例(60%)患者患有非酒精性脂肪性肝炎(NASH)，定义为“存在脂肪变性和炎症征象”。此外，NASH患者的ALT和AST水平显著高于无NASH的患者。然而，两组患者的性别、年龄、BMI和HbA1c无显著差异。
对正十三烷、3-甲基丁腈和1-丙醇这3种挥发性有机化合物(VOC)进行分析使研究者能够区别有和无NASH的患者，敏感性为90%，特异性为69%，受试者工作特征(ROC)曲线下面积为0.77±0.07。VOC分析对NASH的阳性预测值为81%，阴性预测值为82%。相比之下，61例患者的血浆转氨酶评估结果显示，ALT的敏感性为19%，特异性为96%，阳性和阴性预测值分别为88%和43%。进一步评估AST/ALT比值发现，该比值的敏感性为32%，特异性为79%，阳性和阴性预测值分别为70%和43%。
研究者得出结论：VOC的诊断价值明显高于血浆转氨酶，前者误诊的患者更少。采用VOC、ALT和AST/ALT比值预测NASH的结果未反映分别在18%、51%和49%患者中观察到的肝活检结果。采用VOC评估(而非组织学检查)具有其他一些优势，例如可在早期轻度阶段检出NASH，这对于提高治愈率非常关键。此外，肝活检评估需使用一小部分肝脏组织，而呼气VOC检测在非侵入的情况下即可反映全肝功能。
该研究获荷兰SenterNovem创新导向基因组学研究项目和比利时林堡跨国大学资助。研究者声明无经济利益冲突。
随刊述评：VOC生物合成机制有待阐明
西奈山医学院的Scott L. Friedman博士表示，呼气VOC分析技术的预测价值优于转氨酶，值得进一步优化和验证。
然而，该研究的研究者既未阐明这些特异性有机化合物是通过什么代谢通路及在哪些细胞中产生的，也未阐明为什么它们可能与疾病活动性相关。在没有弄清楚这些方面的情况下，这些有机化合物应被视为相关性标志物，而不是真正的生物标志物，因为缺乏与疾病相关通路的机械性关联，而这种关联是定义生物标志物的关键要求(J. Hepatol. 2013;58:j407-8 )。Friedman博士是美沙西丁呼气试验生产商Exalenz Biosciences公司的顾问。
By: HEATHER LINDSEY, Internal Medicine News Digital Network
The analysis of volatile organic compounds in exhaled breath may provide a noninvasive and accurate test for diagnosing nonalcoholic steatohepatitis, according to results from a pilot study published in March.
This test could reduce the number of unnecessary liver biopsies and missed diagnoses associated with assessing plasma transaminase levels, reported Dr. Froukje J. Verdam of Maastricht (the Netherlands) University Medical Center and her associates (J. Hepatol. 2013;58:543-8).
Researchers evaluated breath samples with gas chromatography–mass spectrometry from 65 consecutive overweight or obese patients before they underwent laparoscopic abdominal surgery, between October 2007 and May 2011. These results were compared with histologic analysis of liver biopsies taken intraoperatively and assessments of plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Overall, liver biopsies showed that 39 patients (60%) had nonalcoholic steatohepatitis (NASH), defined as "showing signs of steatosis and inflammation." Additionally, ALT and AST levels were significantly higher in patients with the disease than without. However, "parameters such as gender, age, BMI, and HbA1c did not differ significantly," reported the study authors.
The analysis of three volatile organic compounds (VOCs) – n-tridecane, 3-methylbutanonitrile, and 1-propanol – enabled investigators to distinguish between patients with and without NASH, with a sensitivity of 90%, a specificity of 69%, and an area under the receiver operating characteristic (ROC) curve of 0.77 plus or minus 0.07. The positive predictive value of using VOC analysis for NASH was 81%, while the negative predictive value was 82%.
In comparison, in 61 patients from whom plasma was available, the sensitivity of measuring ALT was 19%, while the specificity was 96%. The positive and negative predictive values of ALT were 88% and 43%, respectively.
Further evaluation of the AST/ALT ratio found that it was 32% sensitive and 79% specific, while positive and negative predictive values were 70% and 43%, respectively.
"It can be concluded that the diagnostic value of VOC is much higher than that of plasma transaminases, resulting in less misdiagnosed patients," wrote the study authors. Prediction of NASH using VOC, ALT, and the AST/ALT ratio did not reflect liver biopsy results in 18%, 51%, and 49% of subjects, respectively.
Using VOC evaluation rather than histologic testing has several other advantages, according to the researchers. "The analysis of exhaled breath can identify NASH presence at an early stage, and early identification in a mild stage is pivotal to enhance the chances of cure," they wrote. "Furthermore, whereas a small part of the liver is considered in the evaluation of biopsies, the breath test used in this study noninvasively reflects total liver function."
Funding for this pilot study was provided by grants from the Dutch SenterNovem Innovation Oriented Research Program on Genomics and the Transnational University Limburg, Belgium. The study authors reported no conflicts of interest.
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VOC biosynthesis needs elucidation
Dr. Scott L. Friedman comments: The study findings are "intriguing," and the performance metrics of the analysis of exhaled VOCs "are promising but not exceptional," wrote Dr. Scott L. Friedman. However, "they well exceed the predictive values of transaminases, so that the technology has value and merits further refinement and validation."
The investigators do "not indicate through what metabolic pathways and in which cells these specific organic compounds are generated, and why they might correlate with disease activity," he added. "Without such insight, the test is a correlative marker rather than a true biomarker since there is no mechanistic link to a disease-related pathway, which is a key requirement for a biomarker."
Dr. Friedman is professor of medicine, liver diseases, at the Mount Sinai School of Medicine in New York. These remarks were adapted from his editorial accompanying this article and another on fatty liver disease and telomerase length (J. Hepatol. 2013;58:j407-8 ). He is a consultant for Exalenz Biosciences, which produces the methacetin breath test.
