S2053 Targeted Breath Biopsy Profiling of Induced Biomarkers Unveils a Metabolic Adaptation in Cirrhosis Toward Alcohol Production

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Introduction: Subjects with chronic liver disease showed higher circulating ethanol levels after fasting or carbohydrates ingestion. However, clinical functional data about the capability of the injured liver to cope with alcohols remain limited. In this study we used exhaled breath analysis to explore the conversion of an alcohol to the corresponding ketone, and a ketone to the corresponding alcohol, to establish the suitability of potential metabolic alterations and identify subjects with cirrhosis using a non-invasive breath test Methods: We selected 2-butanol, and 2-pentanone (the substrates) as an alcohol and a ketone based on their safe human consumption, reported hepatic metabolism, and presence in breath. Hepatic metabolism was confirmed by treating human suspension hepatocytes with 10 ng/µl of 2-butanol, and 2-pentanone to measure their conversion to respectively 2-butanone, and 2-pentanol (the bioproducts) by using headspace analysis coupled with gas-chromatography mass-spectrometry (GC-MS). Clinical metabolism was evaluated by analysing the breath profile of 14 subjects with cirrhosis and 15 controls before and at different timepoints (10 - 120 minutes) after ingestion of 2-butanol (100 mg) and 2-pentanone (100 mg), using Breath Biopsy OMNI Results: Bioproducts were present in primary hepatocytes treated with the substrates and absent in control conditions omitting primary hepatocytes or substrates. After an overnight fasting all the participants showed breath levels of investigated compounds with no differences between healthy and cirrhosis groups (P > 0.05). After ingestion of the substrates, all the subjects showed a > 100-fold increase of investigated compounds within 10 minutes. Subjects with cirrhosis showed higher levels of 2-butanol and 2-pentanol (P < 0.05) compared to controls between 20- and 90-minutes post-administration. An exploratory classification model built on these breath-induced biomarkers at 20 minutes showed an area under the ROC curve of 0.85 Conclusion: 2-butanol and 2-pentanone are metabolized to the corresponding ketone and alcohol in primary hepatocytes. Cirrhosis subjects showed higher breath levels of secondary alcohols independently from administration of the alcohol or the corresponding ketone, suggesting hepatic function is more balanced toward alcohol production compared to controls. This metabolic adaptation may contribute to higher circulating ethanol levels in subjects with chronic liver disease and be exploited in a breath test for cirrhosis detection (see Figure 1).Figure 1.: Boxplots showing breath levels of 2-butanol and 2-pentanone, and their respective hepatic products 2-butanone and 2-pentanol in control and cirrhosis subjects, before and after ingestion of the substrates.

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