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Isoprene in the Exhaled Breath is a Novel Biomarker for Advanced Fibrosis in Patients with Chronic Liver Disease: A Pilot Study.

Alkhouri N, Singh T, Alsabbagh E, Guirguis J, Chami T, Hanouneh I, Grove D, Lopez R, Dweik R - Clin Transl Gastroenterol (2015)

Bottom Line: Bonferroni correction was applied to decrease the false discovery rate.The median breath isoprene level in patients with F3-4 was 13.5[8.7, 24.7] p.p.b. compared with 40.4[26.2, 54.1] for those with F0-2, P value <0.001.Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.

ABSTRACT

Objectives: Analysis of volatile organic compounds (VOCs) in the exhaled breath can identify markers for alcoholic and nonalcoholic fatty liver disease. The aim of this pilot study was to investigate the utility of breath VOCs measured by mass spectrometry to diagnose advanced fibrosis in patients with chronic liver disease (CLD).

Methods: Patients undergoing liver biopsy were recruited. Fibrosis was determined by an experienced pathologist (F0-4) and advanced fibrosis was defined as F3-4. Exhaled breath and plasma samples were collected on the same day of the biopsy. Selective ion flow tube mass spectrometry (SIFT-MS) was used to analyze breath samples. Bonferroni correction was applied to decrease the false discovery rate.

Results: In all, 61 patients were included with a mean age of 50.7±9.9 years and 57% were male. Twenty patients (33%) had advanced fibrosis (F3-4), 44% had chronic hepatitis C, 30% had nonalcoholic fatty liver disease, and 26% had other CLD. SIFT-MS analysis of exhaled breath revealed that patients with advanced fibrosis had significantly lower values of six compounds compared with those without advanced fibrosis, P value <0.002 for all. Isoprene was found to have the highest accuracy for the prediction of advanced fibrosis with an area under the receiver operating characteristics curve of 0.855 (95% confidence interval: 0.762, 0.948). The median breath isoprene level in patients with F3-4 was 13.5[8.7, 24.7] p.p.b. compared with 40.4[26.2, 54.1] for those with F0-2, P value <0.001. Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis.

Conclusions: Isoprene is a potential biomarker for advanced fibrosis that deserves further validation.

No MeSH data available.


Related in: MedlinePlus

Isoprene for the diagnosis of advanced fibrosis: receiver operating characteristics curve. Good accuracy of breath isoprene levels in predicting the presence of advanced fibrosis on liver biopsy. The ideal area under the curve is 1.00. AUC, area under ROC curve; CI, confidence interval; ROC, receiver operating characteristic.
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fig2: Isoprene for the diagnosis of advanced fibrosis: receiver operating characteristics curve. Good accuracy of breath isoprene levels in predicting the presence of advanced fibrosis on liver biopsy. The ideal area under the curve is 1.00. AUC, area under ROC curve; CI, confidence interval; ROC, receiver operating characteristic.

Mentions: Further analysis of these six compounds revealed that isoprene had the highest AUC for predicting the presence of advanced liver fibrosis on biopsy (0.855 (95% confidence interval:0.762–0.948); Table 3 and Figure 2). The likelihood of having advanced fibrosis decreases by 10% for every one unit increase in isoprene (odds ratio (95% confidence interval): 0.90 (0.85, 0.95); P<0.001). An isoprene level more than or equal to 29 p.p.b. would provide specificity, sensitivity, positive, and negative predictive values of 68, 85, 57, and 90%, respectively, for predicting advanced fibrosis. On the other hand, an isoprene level of less than 14.1 p.p.b. would provide specificity, sensitivity, positive, and negative predictive values of 93, 60, 80, and 83%, respectively. Combining these two cutoff values for exhaled breath isoprene, we propose the diagnostic algorithm presented on Figure 3. A cutoff value of 29 p.p.b. was used to maximize sensitivity and rule out the presence of advanced fibrosis. A cutoff of 14.1 p.p.b. was used to maximize specificity and rule in the presence of advanced fibrosis. Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis, which may explain the lower levels in patients with advanced liver disease. Because of the known association between isoprene and cholesterol biosynthesis, we further investigated the association between exhaled isoprene level and plasma cholesterol levels. There was no significant correlation between isoprene and cholesterol (rho=−0.13 (−0.50, 0.23); P=0.46). Median cholesterol levels were 165 [154, 194.5] mg/dl for F0–2 vs. 172.0 [102, 184] mg/dl for F3–4 (P=0.38). None of our patients were on statins in the previous 3 months before liver biopsy. To confirm the endogenous source of isoprene, we used the same SIFT-MS technology to measure levels of isoprene in the headspace of available serum samples that were obtained on the day of liver biopsy (n=33). We found that patients with advanced fibrosis had a trend toward having lower serum levels of isoprene compared with those without advanced fibrosis (18.0 [14.6, 21.6] p.p.b. vs. 13.2 [11.4, 16.6], P value of 0.052) further validating our findings in the exhaled breath. Combining isoprene with other VOCs did not significantly improve the diagnostic accuracy for predicting the presence of advanced fibrosis as shown in the Supplementary Table.


Isoprene in the Exhaled Breath is a Novel Biomarker for Advanced Fibrosis in Patients with Chronic Liver Disease: A Pilot Study.

Alkhouri N, Singh T, Alsabbagh E, Guirguis J, Chami T, Hanouneh I, Grove D, Lopez R, Dweik R - Clin Transl Gastroenterol (2015)

Isoprene for the diagnosis of advanced fibrosis: receiver operating characteristics curve. Good accuracy of breath isoprene levels in predicting the presence of advanced fibrosis on liver biopsy. The ideal area under the curve is 1.00. AUC, area under ROC curve; CI, confidence interval; ROC, receiver operating characteristic.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816250&req=5

fig2: Isoprene for the diagnosis of advanced fibrosis: receiver operating characteristics curve. Good accuracy of breath isoprene levels in predicting the presence of advanced fibrosis on liver biopsy. The ideal area under the curve is 1.00. AUC, area under ROC curve; CI, confidence interval; ROC, receiver operating characteristic.
Mentions: Further analysis of these six compounds revealed that isoprene had the highest AUC for predicting the presence of advanced liver fibrosis on biopsy (0.855 (95% confidence interval:0.762–0.948); Table 3 and Figure 2). The likelihood of having advanced fibrosis decreases by 10% for every one unit increase in isoprene (odds ratio (95% confidence interval): 0.90 (0.85, 0.95); P<0.001). An isoprene level more than or equal to 29 p.p.b. would provide specificity, sensitivity, positive, and negative predictive values of 68, 85, 57, and 90%, respectively, for predicting advanced fibrosis. On the other hand, an isoprene level of less than 14.1 p.p.b. would provide specificity, sensitivity, positive, and negative predictive values of 93, 60, 80, and 83%, respectively. Combining these two cutoff values for exhaled breath isoprene, we propose the diagnostic algorithm presented on Figure 3. A cutoff value of 29 p.p.b. was used to maximize sensitivity and rule out the presence of advanced fibrosis. A cutoff of 14.1 p.p.b. was used to maximize specificity and rule in the presence of advanced fibrosis. Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis, which may explain the lower levels in patients with advanced liver disease. Because of the known association between isoprene and cholesterol biosynthesis, we further investigated the association between exhaled isoprene level and plasma cholesterol levels. There was no significant correlation between isoprene and cholesterol (rho=−0.13 (−0.50, 0.23); P=0.46). Median cholesterol levels were 165 [154, 194.5] mg/dl for F0–2 vs. 172.0 [102, 184] mg/dl for F3–4 (P=0.38). None of our patients were on statins in the previous 3 months before liver biopsy. To confirm the endogenous source of isoprene, we used the same SIFT-MS technology to measure levels of isoprene in the headspace of available serum samples that were obtained on the day of liver biopsy (n=33). We found that patients with advanced fibrosis had a trend toward having lower serum levels of isoprene compared with those without advanced fibrosis (18.0 [14.6, 21.6] p.p.b. vs. 13.2 [11.4, 16.6], P value of 0.052) further validating our findings in the exhaled breath. Combining isoprene with other VOCs did not significantly improve the diagnostic accuracy for predicting the presence of advanced fibrosis as shown in the Supplementary Table.

Bottom Line: Bonferroni correction was applied to decrease the false discovery rate.The median breath isoprene level in patients with F3-4 was 13.5[8.7, 24.7] p.p.b. compared with 40.4[26.2, 54.1] for those with F0-2, P value <0.001.Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.

ABSTRACT

Objectives: Analysis of volatile organic compounds (VOCs) in the exhaled breath can identify markers for alcoholic and nonalcoholic fatty liver disease. The aim of this pilot study was to investigate the utility of breath VOCs measured by mass spectrometry to diagnose advanced fibrosis in patients with chronic liver disease (CLD).

Methods: Patients undergoing liver biopsy were recruited. Fibrosis was determined by an experienced pathologist (F0-4) and advanced fibrosis was defined as F3-4. Exhaled breath and plasma samples were collected on the same day of the biopsy. Selective ion flow tube mass spectrometry (SIFT-MS) was used to analyze breath samples. Bonferroni correction was applied to decrease the false discovery rate.

Results: In all, 61 patients were included with a mean age of 50.7±9.9 years and 57% were male. Twenty patients (33%) had advanced fibrosis (F3-4), 44% had chronic hepatitis C, 30% had nonalcoholic fatty liver disease, and 26% had other CLD. SIFT-MS analysis of exhaled breath revealed that patients with advanced fibrosis had significantly lower values of six compounds compared with those without advanced fibrosis, P value <0.002 for all. Isoprene was found to have the highest accuracy for the prediction of advanced fibrosis with an area under the receiver operating characteristics curve of 0.855 (95% confidence interval: 0.762, 0.948). The median breath isoprene level in patients with F3-4 was 13.5[8.7, 24.7] p.p.b. compared with 40.4[26.2, 54.1] for those with F0-2, P value <0.001. Isoprene is an endogenous VOC that is a byproduct of cholesterol biosynthesis.

Conclusions: Isoprene is a potential biomarker for advanced fibrosis that deserves further validation.

No MeSH data available.


Related in: MedlinePlus