Abstract
The liver plays a pivotal role in a myriad of metabolic processes, including detoxification, glycolipidic storage and export, and protein synthesis. Breath tests employing 13C as stable isotope have been introduced to explore such energy-dependent pathways involving mitochondrial function in the liver. Specific substrates are ketoisocaproic acid, methionine, and octanoic acid. In humans, the application of 13C-breath tests ranges from nonalcoholic and alcoholic liver diseases to liver cirrhosis, hepatocarcinoma, preoperative and postoperative assessment of liver function, and drug-induced liver damage. Studying liver mitochondrial function by 13C-breath tests represents a complementary tool to monitor complex metabolic processes in health and disease.
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References
Lee WS, Sokol RJ (2007) Liver disease in mitochondrial disorders. Semin Liver Dis 27:259–273
Russmann S, Kullak-Ublick GA, Grattagliano I (2009) Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 16:3041–3053
Grattagliano I, Bonfrate L, Diogo CV et al (2009) Biochemical mechanisms in drug-induced liver injury: certainties and doubts. World J Gastroenterol 15:4865–4876
Grattagliano I, Portincasa P, D'Ambrosio G et al (2010) Avoiding drug interactions: here's help. J Fam Pract 59:322–329
Sherlock S, Dooley J (2002) Diseases of the liver and biliary system. Blackwell Science, Oxford
Ziol M, Handra-Luca A, Kettaneh A et al (2005) Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 41:48–54
Curry MP, Afdhal NH (2013) Tests used for the noninvasive assessment of hepatic fibrosis. UpToDate Version 20.0
Castera L, Vergniol J, Foucher J et al (2005) Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 128:343–350
Nadanaciva S, Will Y (2011) New insights in drug-induced mitochondrial toxicity. Curr Pharm Des 17:2100–2112
Pereira CV, Nadanaciva S, Oliveira PJ et al (2012) The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo. Expert Opin Drug Metab Toxicol 8:219–237
Grattagliano I, de Bari O, Bernardo TC et al (2012) Role of mitochondria in nonalcoholic fatty liver disease-from origin to propagation. Clin Biochem 45:610–618
Grattagliano I, Lauterburg BH, Palasciano G et al (2010) (13)C-breath tests for clinical investigation of liver mitochondrial function. Eur J Clin Invest 40(9):843–850
Masuo Y, Imai T, Shibato J et al (2009) Omic analyses unravels global molecular changes in the brain and liver of a rat model for chronic Sake (Japanese alcoholic beverage) intake. Electrophoresis 30:1259–1275
Griffin JL, Nicholls AW (2006) Metabolomics as a functional genomic tool for understanding lipid dysfunction in diabetes, obesity and related disorders. Pharmacogenomics 7:1095–1107
Krahenbuhl L, Ledermann M, Lang C et al (2000) Relationship between hepatic mitochondrial functions in vivo and in vitro in rats with carbon tetrachloride-induced liver cirrhosis. J Hepatol 33:216–223
Michaletz PA, Cap L, Alpert E et al (1989) Assessment of mitochondrial function in vivo with a breath test utilizing alpha-ketoisocaproic acid. Hepatology 10:829–832
Grattagliano I, Vendemiale G, Lauterburg BH (1999) Reperfusion injury of the liver: role of mitochondria and protection by glutathione ester. J Surg Res 86:2–8
Berthold HK, Giesen TA, Gouni-Berthold I (2009) The stable isotope ketoisocaproic acid breath test as a measure of hepatic decarboxylation capacity: a quantitative analysis in normal subjects after oral and intravenous administration. Liver Int 29:1356–1364
Lauterburg BH, Liang D, Schwarzenbach FA et al (1993) Mitochondrial dysfunction in alcoholic patients as assessed by breath analysis. Hepatology 17:418–422
Witschi A, Mossi S, Meyer B et al (1994) Mitochondrial function reflected by the decarboxylation of [13C]ketoisocaproate is impaired in alcoholics. Alcohol Clin Exp Res 18:951–955
Bendtsen P, Hannestad U, Pahlsson P (1998) Evaluation of the carbon 13-labeled Ketoisocaproate breath test to assess mitochondrial dysfunction in patients with high alcohol consumption. Alcohol Clin Exp Res 22:1792–1795
Portincasa P, Grattagliano I, Lauterburg BH et al (2006) Liver breath tests non-invasively predict higher stages of non-alcoholic steatohepatitis. Clin Sci (Lond) 111:135–143
Palmieri VO, Grattagliano I, Minerva F et al (2009) Liver function as assessed by breath tests in patients with hepatocellular carcinoma. J Surg Res 157:199–207
Bonfrate L, Giuliante F, Palasciano G et al (2013) Unexpected discovery of massive liver echinococcosis. A clinical, morphological, and functional diagnosis. Ann Hepatol 12:634–641
Pessayre D, Mansouri A, Haouzi D et al (1999) Hepatotoxicity due to mitochondrial dysfunction. Cell Biol Toxicol 15:367–373
Lauterburg BH, Grattagliano I, Gmur R et al (1995) Noninvasive assessment of the effect of xenobiotics on mitochondrial function in human beings: studies with acetylsalicylic acid and ethanol with the use of the carbon 13-labeled ketoisocaproate breath test. J Lab Clin Med 125:378–383
Danicke S, Diers S (2013) Effects of ergot alkaloids on liver function of piglets as evaluated by the (13)C-methacetin and (13)C-alpha-ketoisocaproic acid breath test. Toxins (Basel) 5:139–161
Storch KJ, Wagner DA, Burke JF et al (1988) Quantitative study in vivo of methionine cycle in humans using [methyl-2H3]- and [1-13C]methionine. Am J Physiol 255:E322–E331
Russmann S, Junker E, Lauterburg BH (2002) Remethylation and transsulfuration of methionine in cirrhosis: studies with L-[H3-methyl-1-C]methionine. Hepatology 36:1190–1196
Armuzzi A, Marcoccia S, Zocco MA et al (2000) Non-Invasive assessment of human hepatic mitochondrial function through the 13C-methionine breath test. Scand J Gastroenterol 35:650–653
Spahr L, Negro F, Leandro G et al (2003) Impaired hepatic mitochondrial oxidation using the 13C-methionine breath test in patients with macrovesicular steatosis and patients with cirrhosis. Med Sci Monit 9:CR6–CR11
Milazzo L, Piazza M, Sangaletti O et al (2005) [13C]Methionine breath test: a novel method to detect antiretroviral drug-related mitochondrial toxicity. J Antimicrob Chemother 55:84–89
Li Y, Boehning DF, Qian T et al (2007) Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J 21:2474–2485
Stuwe SH, Goetze O, Arning L et al (2011) Hepatic mitochondrial dysfunction in Friedreich ataxia. BMC Neurol 11:145
Durr A, Cossee M, Agid Y et al (1996) Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 335:1169–1175
Ghoos YF, Maes BD, Geypens BJ et al (1993) Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test. Gastroenterology 104:1640–1647
Perri F, Bellini M, Portincasa P et al (2010) (13)C-octanoic acid breath test (OBT) with a new test meal (EXPIROGer): toward standardization for testing gastric emptying of solids. Dig Liver Dis 42:549–553
Shalev T, Aeed H, Sorin V et al (2010) Evaluation of the 13C-octanoate breath test as a surrogate marker of liver damage in animal models. Dig Dis Sci 55:1589–1598
Schneider AR, Kraut C, Lindenthal B et al (2005) Total body metabolism of 13C-octanoic acid is preserved in patients with non-alcoholic steatohepatitis, but differs between women and men. Eur J Gastroenterol Hepatol 17:1181–1184
Miele L, Grieco A, Armuzzi A et al (2003) Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13C-octanoate breath test. Am J Gastroenterol 98:2335–2336
van de Casteele M, Luypaerts A, Geypens B et al (2003) Oxidative breakdown of octanoic acid is maintained in patients with cirrhosis despite advanced disease. Neurogastroenterol Motil 15:113–120
Banasch M, Emminghaus R, Ellrichmann M et al (2008) Longitudinal effects of hepatitis C virus treatment on hepatic mitochondrial dysfunction assessed by C-methionine breath test. Aliment Pharmacol Ther 28:443–449
Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 44:88–106
Nakagawa Y, Suzuki T, Kamimura H et al (2006) Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes. Eur J Pharmacol 529:33–39
Trost LC, Lemasters JJ (1997) Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome. Toxicol Appl Pharmacol 147:431–441
Mingatto FE, dos Santos AC, Rodrigues T et al (2000) Effects of nimesulide and its reduced metabolite on mitochondria. Br J Pharmacol 131:1154–1160
Kass GE, Price SC (2008) Role of mitochondria in drug-induced cholestatic injury. Clin Liver Dis 12:27–51, vii
Candelli M, Miele L, Armuzzi A et al (2008) 13C-methionine breath tests for mitochondrial liver function assessment. Eur Rev Med Pharmacol Sci 12:245–249
Duro D, Duggan C, Valim C et al (2009) Novel intravenous (13)C-methionine breath test as a measure of liver function in children with short bowel syndrome. J Pediatr Surg 44:236–240, discussion 240
Bromer MQ, Kantor SB, Wagner DA et al (2002) Simultaneous measurement of gastric emptying with a simple muffin meal using [13C]octanoate breath test and scintigraphy in normal subjects and patients with dyspeptic symptoms. Dig Dis Sci 47:1657–1663
Dawson B, Trapp RG (2001) Basic & clinical biostatistics, vol 3. McGraw-Hill, New York
Hintze J (2013) NCSS 9. NCSS, LLC, Kaysville, UT www.ncss.com. Number Cruncher Statistical System (NCSS), Kaysville, UT
Winchell HS, Wiley K (1970) Considerations in analysis of breath 14CO2 data. J Nucl Med 11:708–710
Banasch M, Ellrichmann M, Tannapfel A et al (2011) The non-invasive (13)C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis. Eur J Med Res 16:258–264
Acknowledgements
This work is partly supported by grants from the University of Bari (ORBA09XZZT, ORBA08YHKX). We are indebted to Carlos Palmeira, Paulo Oliveira and Catia Diogo (Coimbra University, Portugal) for longstanding scientific discussions and for sharing collaboration. We thank Rosa De Venuto, Paola De Benedictis, and Michele Persichella for skillful technical support.
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Grattagliano, I., Bonfrate, L., Lorusso, M., Castorani, L., de Bari, O., Portincasa, P. (2015). Exploring Liver Mitochondrial Function by 13C-Stable Isotope Breath Tests: Implications in Clinical Biochemistry. In: Palmeira, C., Rolo, A. (eds) Mitochondrial Regulation. Methods in Molecular Biology, vol 1241. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1875-1_12
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DOI: https://doi.org/10.1007/978-1-4939-1875-1_12
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