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Breath-Ammonia Testing of Healthy Subjects and Patients with Cirrhosis

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Abstract

Background

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication in both acute and chronic liver disease.

Aims

To establish the utility of a portable noninvasive method to measure ammonia in the breath of healthy subjects and patients with HE.

Methods

The study included 106 subjects: 44 women and 62 men, 51 healthy and 55 cirrhotic. The breath ammonia was measured with an electrochemical sensor and expressed in parts/billion (ppb).

Results

The breath ammonia in healthy subjects had an average value of 151.4 ppb (95% confidence interval [CI]: 149.4–153.4) and the average value in cirrhotic patients was 169.9 ppb (95% CI: 163.5–176.2) (P < 0.0001). In cirrhotic patients with and without HE, the corresponding values were 184.1 ppb (95% CI: 167.7–200.6) and 162.9 ppb (95% CI: 158.8–167.0), respectively (P = 0.0011). Ammonia levels ≥165 ppb permitted a differentiation between healthy and cirrhotic subjects; the area under the receiver operating characteristic (ROC) curve for the ammonia-level values in cirrhotic versus control patients was 0.86 (95% CI: 0.79–0.93). In cirrhotic patients, ammonia levels ≥175 ppb permitted the distinction between patients with and without HE; the area under the ROC curve in cirrhotic patients with versus without HE was 0.83 (95% CI: 0.73–0.94).

Conclusion

A portable sensor for measuring breath ammonia can be developed. If the results of the present study are confirmed, breath-ammonia determinations could produce a significant impact on the care of patients with cirrhosis and could even include the possibility of self-monitoring.

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References

  1. Jacobs MH. Some aspects of cell permeability to weak electrolytes. Cold Spring Harb Symp Quant Biol. 1940;8:30–39.

    CAS  Google Scholar 

  2. Kleiner D. The transport of NH3 and NH4+ across biological membranes. Biochim Biophys Acta. 1981;639:41–52.

    PubMed  CAS  Google Scholar 

  3. Watanabe A, Fujiwara M, Tominaga S, Nagashima H. Elevation of ammonia contents in the cerebral hemisphere under the blood–brain barrier opening. Hiroshima J Med Sci. 1987;36:415–416.

    PubMed  CAS  Google Scholar 

  4. Cooper AJ, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev. 1987;67:440–519.

    PubMed  CAS  Google Scholar 

  5. Ferenci P, Lockwood A, Mullen K, Tarter R, et al. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716–721.

    Article  PubMed  Google Scholar 

  6. Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, Morgan MY; International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Review article: the design of clinical trials in hepatic encephalopathy—an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. 2011;33:739–747.

    Article  PubMed  CAS  Google Scholar 

  7. Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007;22:125–138.

    Article  PubMed  CAS  Google Scholar 

  8. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40:247–254.

    Article  PubMed  CAS  Google Scholar 

  9. Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS. New concepts in the mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis. 2007;22:219–234.

    Article  PubMed  CAS  Google Scholar 

  10. Schliess F, Görg B, Häussinger D. Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm. Biol Chem. 2006;387:1363–1370.

    Article  PubMed  CAS  Google Scholar 

  11. Ahboucha S, Butterworth RF. The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy. Metab Brain Dis. 2007;22:291–308.

    Article  PubMed  CAS  Google Scholar 

  12. Qadri AM, Ogunwale BO, Mullen KD. Can we ignore minimal hepatic encephalopathy any longer? Hepatology. 2007;45:547–548.

    Article  PubMed  Google Scholar 

  13. Talwalkar JA, Kamath PS. Influence of recent advances in medical management on clinical outcomes of cirrhosis. Mayo Clin Proc. 2005;80:1501–1508.

    Article  PubMed  Google Scholar 

  14. Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther. 2007;25:3–9.

    Article  PubMed  Google Scholar 

  15. Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998;28:45–49.

    Article  PubMed  CAS  Google Scholar 

  16. Prasad S, Dhiman RK, Duseja A, Chawla YK, et al. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 2007;45:549–559.

    Article  PubMed  Google Scholar 

  17. Bajaj JS, Hafeezullah M, Hoffmann RG, Varma RR, et al. Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy. Hepatology. 2008;47:596–604.

    Article  PubMed  Google Scholar 

  18. Bajaj JS, Saeian K, Hafeezullah M, Hoffmann RG, Hammeke TA. Patients with minimal hepatic encephalopathy have poor insight into their driving skills. Clin Gastroenterol Hepatol. 2008;6:1135–1139.

    Article  PubMed  Google Scholar 

  19. Bajaj JS, Hafeezullah M, Zadvornova Y, Martin E, et al. The effect of fatigue on driving skills in patients with hepatic encephalopathy. Am J Gastroenterol. 2009;104:898–905.

    Article  PubMed  Google Scholar 

  20. Quero JC, Schalm SW. Subclinical hepatic encephalopathy. Semin Liver Dis. 1996;16:321–328.

    Article  PubMed  CAS  Google Scholar 

  21. Tarter RE, Hegedus AM, Van Thiel DH, Schade RR, Gavaler JS, Starzl TE. Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology. 1984;86:1421–1427.

    PubMed  CAS  Google Scholar 

  22. Quero JC, Hartmann IJ, Meulstee J, Hop WC, Schalm SW. The diagnosis of subclinical hepatic encephalopathy in patients with cirrhosis using neuropsychological tests and automated electroencephalogram analysis. Hepatology. 1996;24:556–560.

    Article  PubMed  CAS  Google Scholar 

  23. Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, Schalm SW. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998;28:45–49.

    Article  PubMed  CAS  Google Scholar 

  24. Weissenborn K, Rückert N, Hecker H, Manns MP. The number connection tests A and B: interindividual variability and use for the assessment of early hepatic encephalopathy. J Hepatol. 1998;28:646–653.

    Article  PubMed  CAS  Google Scholar 

  25. Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci. 2000;45:1549–1552.

    Article  PubMed  CAS  Google Scholar 

  26. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997;337:473–479.

    Article  PubMed  CAS  Google Scholar 

  27. Kircheis G, Knoche A, Hilger N, Manhart F, Schnitzler A, Schulze H, Häussinger D. Hepatic encephalopathy and fitness to drive. Gastroenterology. 2009;137:1706–1715.

    Article  PubMed  Google Scholar 

  28. Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology. 2009;50:1175–1183.

    Article  PubMed  Google Scholar 

  29. Bustamante J, Rimola A, Ventura PJ, Navasa M, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999;30:890–895.

    Article  PubMed  CAS  Google Scholar 

  30. Oberti F, Valsesia E, Pilette C, Rousselet MC, Bedossa P, Aubé C, Gallois Y, Rifflet H, Maïga MY, Penneau-Fontbonne D, Calès P. Noninvasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology. 1997;113:1609–1616.

    Article  PubMed  CAS  Google Scholar 

  31. Wagner C, Traud W. On the interpretation of corrosion processes through the superposition of electrochemical partial processes and on the potential of mixed electrodes. Z Elektrochem Ang Physik Chemie. 1938;44:391–402.

    CAS  Google Scholar 

  32. Stern M, Geary AL. Electrochemical polarization. I. A theoretical analysis of the shape of polarization curves. J Electrochem Soc. 1957;104:56–63.

    Article  CAS  Google Scholar 

  33. Robin ED, Travis DM, Bromberg PA, Forkner CE Jr, Tyler JM. Ammonia excretion by mammalian lung. Science. 1959;129:270–271.

    Article  PubMed  CAS  Google Scholar 

  34. Jacquez JA, Poppell JW, Jeltsch R. Partial pressure of ammonia in alveolar air. Science. 1959;129:269–270.

    Article  PubMed  CAS  Google Scholar 

  35. Raichle ME, Larson KB. The significance of the NH3–NH4+ equilibrium on the passage of 13N-ammonia from blood to brain. A new regional residue detection model. Circ Res. 1981;48:913–937.

    PubMed  CAS  Google Scholar 

  36. Ishida H, Satou T, Tsuji K, Kawashima N, Takemura H, Kosaki Y, Shiratori S, Agishi T. The breath ammonia measurement of the hemodialysis with a QCM-NH3 sensor. Biomed Mater Eng. 2008;18:99–106.

    PubMed  CAS  Google Scholar 

  37. Toda K, Li J, Dasgupta PK. Measurement of ammonia in human breath with a liquid-film conductivity sensor. Anal Chem. 2006;78:7284–7291.

    Article  PubMed  CAS  Google Scholar 

  38. Turner C, Spanel P, Smith D. A longitudinal study of ammonia, acetone and propanol in the exhaled breath of 30 subjects using selected ion flow tube mass spectrometry, SIFT-MS. Physiol Meas. 2006;27:321–337.

    Article  PubMed  Google Scholar 

  39. DuBois S, Eng S, Bhattacharya R, Rulyak S, Hubbard T, Putnam D, Kearney DJ. Breath ammonia testing for diagnosis of hepatic encephalopathy. Dig Dis Sci. 2005;50:1780–1784.

    Article  PubMed  CAS  Google Scholar 

  40. Wakabayashi H, Kuwabara Y, Murata H, Kobashi K, Watanabe A. Measurement of the expiratory ammonia concentration and its clinical significance. Metab Brain Dis. 1997;12:161–169.

    Article  PubMed  CAS  Google Scholar 

  41. Brooks SM, Haight RR, Gordon RL. Age does not affect airway pH and ammonia as determined by exhaled breath measurements. Lung. 2006;184:195–200.

    Article  PubMed  CAS  Google Scholar 

  42. Shimamoto C, Hirata I, Katsu K. Breath and blood ammonia in liver cirrhosis. Hepatogastroenterology. 2000;47:443–445.

    PubMed  CAS  Google Scholar 

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Acknowledgments

We are indebted to Micaela Zicavo and Alejo Adrover, students from the National University of La Plata School of Medicine, for their assistance with the ammonia measurements, and to Ms. Marina Pascual for her help in preparing the manuscript.

Conflict of interest

The authors who have taken part in this study declare that they do not have anything to disclose regarding funding or any conflicts of interest with respect to this manuscript.

Author information

Authors and Affiliations

  1. Hepatology Centre, Calle 37 Nro 926, B1902AWL, La Plata, Argentina

    R. Adrover & D. Cocozzella

  2. Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC”, Ciudad Autónoma de Buenos Aires, Azcuenaga 1057, Piso 6, Dto B, Buenos Aires, Argentina

    E. Ridruejo

  3. Gastroenterology Service, Hospital San Roque de Gonnet, Calle 508 y 19, Gonnet, (1897), La Plata, Argentina

    R. Adrover, D. Cocozzella, A. García & J. Rome

  4. CONICET, Calle 37 Nro 926, B1902AWL, La Plata, Argentina

    J. J. Podestá

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  1. R. Adrover
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  2. D. Cocozzella
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  3. E. Ridruejo
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  4. A. García
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Correspondence to R. Adrover.

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Adrover, R., Cocozzella, D., Ridruejo, E. et al. Breath-Ammonia Testing of Healthy Subjects and Patients with Cirrhosis. Dig Dis Sci 57, 189–195 (2012). https://doi.org/10.1007/s10620-011-1858-9

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  • DOI: https://doi.org/10.1007/s10620-011-1858-9

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