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

Table 1 Summary of the main volatile organic compounds found in the exhaled breath of patients with liver cirrhosis

Compounds and molecules	Metabolic disturbances
Nitrogen derivatives
Ammonia[14]	Altered urea cycle
Trimethylamine[29]	Reduced hepatic catabolism of trimethylamine and/or increased degradation and absorption of dietary phosphatidylcholine and choline mediated by altered intestinal microbiome
Ketones[16]	Increased insulin resistance, hepatic glycogen exhaustion, hepatic gluconeogenesis impairment
Sulfur derivatives[8]	Incomplete metabolism of sulfur-containing amino acids in the transamination pathway
Dimethylsulfide[12]	Main responsible for fetor hepaticus
Alkanes, alkenes, terpenes and aliphatic acids[29]	Lipid peroxidation mediated by oxygen radical produced by hepatic CYP activity
Ethane and pentane[30]	More typical of alcohol induced liver injury
Limonene[13]	Impaired biotransformation by CYP2C (partially dependent on dietary intake of citrus fruits and vegetable)
Acetic and propionic acid[9]	Reduced hepatic metabolism of short chain fatty acids produced by gut microbiome
Alcohols
Methanol[22]	Pectin degradation; its levels are partially dependent on dietary intake of fruits and on a variable role of intestinal microbiome
Ethanol[31]	More typical of NAFLD, even in complete absence of alcohol consumption; possible role of intestinal microbiome in the production of ethanol in obese patients

CYP: Cytochrome P450 enzyme activity; NAFLD: Nonalcoholic fatty liver disease.

Table 2 Discriminative capacities of exhaled breath analysis for clinically relevant applications in hepatology

Study (year)	Methods of breath analysis	Population	Discriminative capacities
LC diagnosis
Van den Velde et al[17] (2008)	GC-MS	52 LC vs 50 HC	Sens 100%, spec 70%
Netzer et al[18] (2009)	IMR-MS	37 LC vs 35 HC	AUC 0.84
Millonig et al[19] (2010)	IMR-MS	37 LC vs 25 HC	AUC 0.88
Dadamio et al[20] (2012)	GC-MS	35 LC vs 49 HC	Sens 82%-88%, spec 96%-100%
Khalid et al[21] (2013)	GC-MS	34 LC vs 7 HC	Sens 100%, spec 86%
Morisco et al[22] (2013)	PTR-MS	12 LC vs 14 HC	AUC 0.88
Fernández Del Río et al[23] (2015)	PTR-MS	31 LC vs 30 HC	Sens 97%, spec 70%, AUC 0.95
Pijls et al[24] (2016)	GC-MS	34 LC vs 87 CLD	Sens 83%, spec 87%, AUC 0.90
De Vincentis et al[25] (2016)	e-nosea	65 LC vs 39 CLD	Sens 88%, spec 69%
Liver function
Morisco et al[22] (2013)	PTR-MS	6 CPC B-C vs 6 CPC A	AUC 0.92
De Vincentis et al[25] (2016)	e-nosea	48 CPC A-B vs 17 CPC C	Sens 88%, spec 64%
De Vincentis et al[26] (2017)	e-nosea	89 LC	aHR 2.8, 95%CI 1.1-7 for mortality and aHR 2.2, 95%CI 1.1-4.2, for hospitalization (analysis adjusted for all potential confounder including CPC and MELD)
NAFLD—NASH
Netzer et al[18] (2009)	IMR-MS	34 NAFLD vs 35 HC	AUC 0.90
Netzer et al[18] (2009)	IMR-MS	34 NAFLD vs 20 AFLD	AUC 0.92
Millonig et al[19] (2010)	IMR-MS	34 NAFLD vs 35 HC	AUC 0.96
Millonig et al[19] (2010)	IMR-MS	34 NAFLD vs 20 AFLD	AUC 0.95
Verdam et al[28] (2013)	GC-MS	39 NASH vs 26 HC	AUC 0.77
Hepatic encephalopathy
Khalid et al[21] (2013)	GC-MS	11 LC with HE vs 23 LC	Sens 91%, spec 87%, AUC 88%
Arasaradnam et al[27] (2016)	e-nose+	22 LC with HE vs 20 HC	Sens 88%, spec 73%, AUC 0.84
Arasaradnam et al[27] (2016)	e-nose+	13 LC with overt HE vs 9 with covert HC	Sens 79%, spec 50%, AUC 0.71
HCC
Qin et al[32] (2010)	GC-MS	30 HCC vs 36 HC	Sens 83%, spec 92%, AUC 0.75
Qin et al[32] (2010)	GC-MS	30 HCC vs 27 LC	Sens 70%, spec 70%, AUC 0.93

^aBIONOTE e-nose, biosensor-based system for mimicking multisensorial nose, tongue and eyes. + uvFAIMS e-nose, ultra-violet field asymmetric ion mobility spectroscopy. LC: Liver cirrhosis; CPC: Child-Pugh class; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; AFLD: Alcoholic fatty liver disease; GC-MS: Gas chromatography mass spectrometry; PTR-MS: Proton transfer reaction mass spectrometry; IMR-MS: Ion molecule reaction mass spectrometry; HCC: Hepatocellular carcinoma; HE: Hepatic encephalopathy; AUC: Area under the receiver operating characteristic curve; Sens: Sensitivity; Spec: Specificity; N/A: Not available; aHR: Adjusted hazard ratio; CI: Confidence interval; MELD: Model for end-stage of liver disease.