## 3 The Metabolites of EB Volatiles
### Ketones  
#### 3.2.1 Acetone  
Acetone is one of the most notable ketone produced by the human metabolism and also a major constituent of human breath. Different mechanisms can lead to its formation. It is absorbed in the body from exogenous sources of contamination, such as food, effluents from chemical industries. Endogenously, acetone can be produced in the hepatocytes through the decarboxylation of excess Acetyl-CoA (Figure 3), but any metabolic change involving an increase in fatty acid oxidation (exercising, fasting, food consumption, weight loss, cancer, and also protein metabolism) results in the formation of ketone bodies, like acetacetate, \(\beta\)-hydroxybutyrate and acetone. In turn, the spontaneous decarboxylation of acetoacetate can also yield more acetone. Remarkably, acetone is the ketone body produced in smaller quantities. Its higher volatility, however, make it easily detectable from breath, urine and skin. In the uncontrolled diabetes mellitus patient's breath, for instance, acetone concentrations are particularly elevated, constituting an easy way to assess the treatment success and a supporting disease monitoring approach, when combined with the regular glucose level checking [184; 185; 186]. In this context, [PERSON] _et al._ also reported that patients with type 1 diabetes have excess acetone in their breath [75]. In turn, [PERSON] _et al._, studied type 2 diabetic patients undergoing a long term dietary modification programme and observed that breath acetone concentrations vary between 160 and 862 ppb [137]. Nevertheless, acetone can not be considered as a marker of diabetes mellitus, but instead of ketone bodies formation. In turn, ketone bodies are a measure of blood glucose levels. Acetone variations have been described in many other diseases and clinical conditions. [PERSON] _et al._, for instance, studied overweight and obese children with Non-Alcoholic Fatty Liver Disease (NAFLD) and found many VOCs, including breath acetone, in significantly higher concentrations [134]. In another study, on liver disease, [PERSON] _et al._ were able to distinguish between patients with Alcoholic Hepatitis (AH), acute decompensation and individuals without liver disease using several breath metabolite levels, mainly breath acetone [135]. [PERSON] _et al._ found higher EB acetone concentrations in Heart Failure (HF) patients as compared to healthy control volunteers. In this study, they exhaustively monitored the condition of HF in a large sample size and reported breath acetone as a new biomarker of HF severity [132]. Overall, given the several sources and situations that can lead to an increase in the concentration of EB acetone, this ketone can hardly be considered as a biomarker of a particular disease or clinical condition. Nevertheless, taking together with additional parameters, it provides very relevant information about the human metabolism.  
Figure 3: Overview of the methodologies most used in exhaling breath (EB) analysis and comparison of some analytical features, as limits of detection, sensitivity and specificity. Additional inputs as time of analysis and simplicity are also included. Abbreviations used: FID—flame ionization detection; GC—gas chromatography; MCC-IMS—multi capillary column ion mobility spectrometry; POC—point of care; PTR-TOF-MS—proton transfer reaction with time-of-flight mass spectrometry; SIFT-MS—Selected ion flow tube mass spectrometry.