Limonene in exhaled breath is elevated in hepatic encephalopathy

Abstract

Breath samples were taken from 31 patients with liver disease and 30 controls in a clinical setting and proton transfer reaction quadrupole mass spectrometry (PTR-Quad-MS) used to measure the concentration of volatile organic compounds (VOCs). All patients had cirrhosis of various etiologies, with some also suffering from hepatocellular cancer (HCC) and/or hepatic encephalopathy (HE). Breath limonene was higher in patients with No-HCC than with HCC, median (lower/upper quartile) 14.2 (7.2/60.1) versus 3.6 (2.0/13.7) and 1.5 (1.1/2.3) nmol mol−1 in controls. This may reflect disease severity, as those with No-HCC had significantly higher UKELD (United Kingdom model for End stage Liver Disease) scores. Patients with HE were categorized as having HE symptoms presently, having a history but no current symptoms and having neither history nor current symptoms. Breath limonene in these groups was median (lower/upper quartile) 46.0 (14.0/103), 4.2 (2.6/6.4) and 7.2 (2.0/19.1) nmol mol−1, respectively. The higher concentration of limonene in those with current symptoms of HE than with a history but no current symptoms cannot be explained by disease severity as their UKELD scores were not significantly different. Longitudinal data from two patients admitted to hospital with HE show a large intra-subject variation in breath limonene, median (range) 18 (10–44) and 42 (32–58) nmol mol−1.

Breath Biopsy Assessment of Liver Disease Using an Exogenous Volatile Organic Compound—Toward Improved Detection of Liver Impairment

“…The unbalanced sex ratio within each group reflects the higher prevalence of HCC in male patients ( 26 ). Across all subjects, the exhaled limonene levels were not affected by sex ( P value = 0.308), as previously described ( 17 , 27 ). Significant differences in age were observed between the study groups ( P values: 0.019, 0.006, and 0.0002, respectively, for cirrhosis vs healthy, HCC+cirrhosis vs healthy, and cirrhosis vs HCC+cirrhosis).…”

“…This reduction is attributed to the downregulation of CYP2C9 and CYP2C19, which, in turn, increases the half-life of limonene in the bloodstream, leading to higher abundance in the breath ( 13 – 18 ). O'Hara et al ( 17 ) found a moderate increase of breath limonene in patients affected by HCC with underlying cirrhosis. Furthermore, proteomic profiling of resected early-stage liver primary tumors and comparison with paired non-tumor liver tissues showed a general downregulation of the CYP 450 system, including CYP2C9 and CYP2C19, in the cancer tissues ( 19 ).…”

Targeted breath analysis: exogenous volatile organic compounds (EVOC) as metabolic pathway-specific probes

“…Limonene is a monoterpene contained in most plant-based foods, especially citrus fruits. High limonene secretion in the breath of cirrhotic patients is the result of reduced limonene clearance from the bloodstream due to dysfunctional biotransformation in the liver [72,74]. These results suggest that exogenous limonene introduced through diet could reveal differences in liver function via measurement of limonene secretion in breath.…”

“…The evidence mentioned above about the association between breath levels of limonene and liver dysfunction [72,74] as well as other studies that clearly indicates that washout curves of administered exogenous VOCs can be used for assessing metabolic function and pharmacokinetics in vivo [93,94]. Yet, the inability to control limonene intake in the general population complicates the definition of threshold values of breath limonene for the identification of liver dysfunction in this application.…”

Assessment of breath volatile organic compounds in acute cardiorespiratory breathlessness: a protocol describing a prospective real-world observational study

“…Proton Transfer Reaction Time-of-Flight Mass Spectromery (PTR-ToF-MS) is a real-time technique, capable of simultaneously measuring the evolution of multiple gas metabolites from a single breath. It has been used for the identification of potential useful VOC biomarkers for diagnosis of a variety of diseases including various cancers,63–65 liver disease66 67 and respiratory disease 68. It has several advantages in clinical settings, such as the speed of sampling, the instant result achieved and the lack of need for sample storage or shipping.…”