Exhaled breath analysis in hepatology: State-of-the-art and perspectives

Abstract

Liver disease is characterized by breath exhalation of peculiar volatile organic compounds (VOCs). Thanks to the availability of sensitive technologies for breath analysis, this empiric approach has recently gained increasing attention in the context of hepatology, following the good results obtained in other fields of medicine. After the first studies that led to the identification of selected VOCs for pathophysiological purposes, subsequent research has progressively turned towards the comprehensive assessment of exhaled breath for potential clinical application. Specific VOC patterns were found to discriminate subjects with liver cirrhosis, to rate disease severity, and, eventually, to forecast adverse clinical outcomes even beyond existing scores. Preliminary results suggest that breath analysis could be useful also for detecting and staging hepatic encephalopathy and for predicting steatohepatitis in patients with nonalcoholic fatty liver disease. However, clinical translation is still hampered by a number of methodological limitations, including the lack of standardization and the consequent poor comparability between studies and the absence of external validation of obtained results. Given the low-cost and easy execution at bedside of the new technologies (e-nose), larger and well-structured studies are expected in order to provide the adequate level of evidence to support VOC analysis in clinical practice.

Keywords: Breath print; Electronic nose; Exhaled breath analysis; Gas chromatography; Hepatic encephalopathy; Liver cirrhosis; Nonalcoholic fatty liver disease.

Figure 1

Schematic representation of volatile organic compounds origin in chronic liver disease and of the main technologies for exhaled breath analysis. Many pathophysiological processes can be altered during the course of chronic liver disease, leading to the production of specific VOCs. Oxidative stress secondary to hepatic inflammation can induce the production of many derivatives of cell membranes peroxidation. With advancing liver fibrosis, other VOCs sources can be represented by many other metabolic pathways that can be deranged with progressive hepatocellular failure. Peculiar VOCs also derive from the gut microbiome or directly from peripheral tissues, bypassing the liver through portosystemic shunts, typical of liver cirrhosis. After exhaled through the breath, VOCs can be sampled, pre-concentrated and stored thanks to dedicated procedures that have been detailed elsewhere[6]. Then, exhaled breath analysis can be carried out through different techniques: (1) The classical analytic techniques based on GC-MS; (2) The gas sensor arrays, commonly dubbed e-noses. Each method has its own pros and cons. Analytical techniques have the advantage of exactly identifying the chemical structure of VOCs, but they are expensive and require long time and high economic resources to be performed on large scale. Conversely, e-noses are portable, cheaper, and easier to perform even in elderly and disabled patients but are less selective and cannot identify the chemical structure of each VOC. Given their different features, each technique is preferable in different research or clinical scenarios, as explained in the text. GC-MS: Gas chromatography and mass spectrometry; VOCs: Volatile organic compounds.