Volatile Biomarkers in Breath Associated With Liver Cirrhosis - Comparisons of Pre- and Post-liver Transplant Breath Samples.
BACKGROUND
The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics.


OBJECTIVE
To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful.


METHODS
A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the post-transplant period.


RESULTS
Seven volatiles were elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2-pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics.


CONCLUSIONS
Limonene, methanol and 2-pentanone are breath markers for a cirrhotic liver. This study raises the potential to investigate these volatiles as markers for early-stage liver disease. By monitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed.
School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK.
R
R
Fernández Del Río
School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK.
M E
ME
O'Hara
Department of Hepatology, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK.
A
A
Holt
Critical Care and Anaesthesia, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK.
P
P
Pemberton
Department of Hepatology, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK.
T
T
Shah
Critical Care and Anaesthesia, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK.
T
T
Whitehouse
School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK.
C A
CA
Mayhew
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D001944:Breath Tests / Q000379:methods*; D053138:Cyclohexenes / Q000032:analysis; D005260:Female; D006801:Humans; D000077222:Limonene; D008103:Liver Cirrhosis / Q000175:diagnosis*; D016031:Liver Transplantation; D008297:Male; D000432:Methanol / Q000032:analysis; D008875:Middle Aged; D010422:Pentanones / Q000032:analysis; D012372:ROC Curve; D013729:Terpenes / Q000032:analysis; D014835:Volatilization
D015415:Biomarkers; D053138:Cyclohexenes; D010422:Pentanones; D013729:Terpenes; D000077222:Limonene; C076402:2-pentanone; D000432:Methanol
AID, autoimmune liver disease; ALD, alcoholic liver disease; AUROC, area under receiver operator curve; BMI, body mass index; Breath analysis; CD, cryptogenic disease; Cirrhosis; Diagnosis limonene; GC, gas chromatography; HBV, hepatitis B virus; HCC, hepatocellular cancer; HCV, hepatitis C virus; ITU, intensive treatment unit; LQ, lower quartile; Liver transplant; MS, mass spectrometry; OPU, out-patient clinic; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PTR-MS; PTR-MS, proton transfer reaction mass spectrometry; ROC, Receiver operating characteristics; TAC, transplant assessment clinic; TE, transient elastography; UKELD, United Kingdom model for end-stage liver disease; UQ, upper quartile; VMR, volume mixing ratio; VOC, volatile organic compounds; Volatile organic compounds; ppbv, parts per billion by volume; ppmv, parts per million by volume