¹³C-basierte Atemtests in der Leberfunktionsdiagnostik

Zusammenfassung

Konventionelle laborchemische Surrogatparameter geben indirekte Hinweise auf den Metabolismus oder die Syntheseleistung hepatischer Zellsysteme. ¹³C-basierte Atemtests erweitern das diagnostische Spektrum um die Aussicht, Enzymsysteme und medikamentöse Interaktionen relativ gezielt nichtinvasiv charakterisieren zu können. Wir geben einen Überblick über die bisher verfügbaren verschiedenen Testsysteme sowie den möglichen Stellenwert in der hepatologischen Diagnostik.

Abstract

Routine work-up of hepatic diseases is performed by regular laboratory tests which indicate changes in the metabolic capacity of various hepatic cellular systems. A ¹³C-based breath test may offer further selective characterisation of hepatic enzymes by means of a non-invasive technique. We present an overview on current test systems and their potential relevance in the assessment of hepatic diseases.

Schlüsselwörter

Leberfunktion - Atemtest - stabile Isotope - Hepatitis - Leberzirrhose - Fibrose

Key words

Liver function - breath test - stable isotopes - hepatitis - liver cirrhosis - fibrosis

Literatur

• 1 Brockmoller J, Roots I. Assessment of liver metabolic function. Clinical implications.  Clin Pharmacokinet. 1994;  27 216-248
• 2 Armuzzi A, Candelli M, Zocco M A. et al . Review article: breath testing for human liver function assessment.  Aliment Pharmacol Ther. 2002;  16 1977-1996
• 3 Caspary W F. Use of breath analysis in diagnosis of liver function.  Z Gastroenterol. 1978;  16 188-197
• 4 Herold C, Berg P, Kupfal D. et al . Parameters of microsomal and cytosolic liver function but not of liver perfusion predict portal vein velocity in noncirrhotic patients with chronic hepatitis C.  Dig Dis Sci. 2000;  45 2233-2237
• 5 Barth E, Tugtekin I, Weidenbach H. et al . Determination of 13CO2/12CO2 ratio by IRMS and NDIRS.  Isotopes Environ Health Stud. 1998;  34 209-213
• 6 Savarino V, Landi F, Dulbecco P. et al . Isotope ratio mass spectrometry (IRMS) versus laser-assisted ratio analyzer (LARA): a comparative study using two doses of.  Dig Dis Sci. 2000;  45 2168-2174
• 7 Braden B, Haisch M, Duan L P. et al . Clinically feasible stable isotope technique at a reasonable price: analysis of 13CO2/12CO2-abundance in breath samples with a new isotope selective-nondispersive infrared spectrometer.  Z Gastroenterol. 1994;  32 675-678
• 8 Adamek R J, Goetze O, Boedeker C. et al . 13C-methacetin breath test: isotope-selective nondispersive infrared spectrometry in comparison to isotope ratio mass spectrometry in volunteers and patients with liver cirrhosis.  Z Gastroenterol. 1999;  37 1139-1143
• 9 Gisbert J P, Gomollon F, Dominguez-Munoz J E. et al . Comparison be­tween two 13C-urea breath tests for the diagnosis of Helicobacter pylori infection: isotope ratio mass spectrometer versus infrared spectrometer.  Gastroenterol Hepatol. 2003;  26 141-146
• 10 Braden B, Gelbmann C, Dietrich C F. et al . Qualitative and quantitative clinical evaluation of the laser-assisted ratio analyser for detection of Helicobacter pylori infection by (13)C-urea breath tests.  Eur J Gastroenterol Hepatol. 2001;  13 807-810
• 11 Hepner G W, Vesell E S. Quantitative assessment of hepatic function by breath analysis after oral administration of (14C)aminopyrine.  Ann Intern Med. 1975;  83 632-638
• 12 Kotake A N, Starr R M. The in vivo evaluation of the effect of age and sex on the developmental profile of aminopyrine N-demethylase activity in the newborn rat.  Drug Metab Dispos. 1982;  10 259-263
• 13 Heit W. Pyrazolone drugs and agranulocytosis.  Agents Actions Suppl. 1986;  19 283-289
• 14 Fowler P D. Aspirin, paracetamol and non-steroidal anti-inflammatory drugs. A comparative review of side effects.  Med Toxicol Adverse Drug Exp. 1987;  2 338-366
• 15 Saunders J B, Lewis K O, Paton A. Early diagnosis of alcoholic cirrhosis by the aminopyrine breath test.  Gastroenterology. 1980;  79 112-114
• 16 Merkel C, Morabito A, Sacerdoti D. et al . Updating prognosis of cirrhosis by Cox’s regression model using Child-Pugh score and aminopyrine breath test as time-dependent covariates.  Ital J Gastroenterol Hepatol. 1998;  30 276-282
• 17 Saunders J B, Wright N, Lewis K O. Predicting outcome of paracetamol poisoning by use 14C-aminopyrine breath test.  Br Med J. 1980;  280 279-280
• 18 Giannini E, Fasoli A, Chiarbonello B. et al . 13C-aminopyrine breath test to evaluate severity of disease in patients with chronic hepatitis C virus infection.  Aliment Pharmacol Ther. 2002;  16 717-725
• 19 Herold C, Heinz R, Niedobitek G. et al . Quantitative testing of liver function in relation to fibrosis in patients with chronic hepatitis B and C.  Liver. 2001;  21 260-265
• 20 Fasoli A, Giannini E, Botta F. et al . 13CO2 excretion in breath of normal subjects and cirrhotic patients after 13C-aminopyrine oral load. Comparison with MEGX test in functional differentiation between chronic hepatitis and liver cirrhosis.  Hepatogastroenterology. 2000;  47 234-238
• 21 Wensing G, Lotterer E, Link I. et al . Urinary sodium balance in patients with cirrhosis: relationship to quantitative parameters of liver func­tion.  Hepatology. 1997;  26 1149-1155
• 22 Wensing G, Sabra R, Branch R A. Relationship between oxidative hepatic metabolism, urinary sodium excretion and sympathetic nerve activity in experimental cirrhosis in the rat.  Z Gastroenterol. 1995;  33 1-4
• 23 Baker A L, Krager P S, Kotake A N. et al . The aminopyrine breath test does not correlate with histologic disease severity in patients with cholestasis.  Hepatology. 1987;  7 464-467
• 24 Herold C, Ganslmayer M, Deynet C. et al . Quantitative testing of liver function compared to prognostic scores in patients with primary biliary cirrhosis.  Liver. 2002;  22 159-165
• 25 Hepner G W, Vesell E S. Assessment of aminopyrine metabolism in man by breath analysis after oral administration of 14C-aminopyrine. Effects of phenobarbital, disulfiram and portal cirrhosis.  N Engl J Med. 1974;  291 1384-1388
• 26 Herz R, Koelz H R, Haemmerli U P. et al . Inhibition of hepatic demethylation of aminopyrine by oral contraceptive steroids in humans.  Eur J Clin Invest. 1978;  8 27-30
• 27 Dossing M, Pilsgaard H, Rasmussen B. et al . Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism.  Eur J Clin Pharmacol. 1983;  25 215-222
• 28 Herold C, Ganslmayer M, Ocker M. et al . Inducibility of microsomal liver function may differentiate cirrhotic patients with maintained compared with severely compromised liver reserve.  J Gastroenterol Hepatol. 2003;  18 445-449
• 29 Van Vlierberghe H, Van Durme F, Verdievel H. et al . Influence of low-dose oral contraceptives, alcohol, and grapefruit on.  Dig Dis Sci. 2001;  46 133-139
• 30 Schneider J F, Schoeller D A, Schreider B D. et al .Use of 13C-phenacetin and 13C-methacetin for the detection of alterations in hepatic drug metabolism. Klein ER, Klein PD Stable Isotopes: Proceedings of the Third International Conference New York; Academic Press 1979: 507-516
• 31 Klatt S, Taut C, Mayer D. et al . Evaluation of the 13C-methacetin breath test for quantitative liver function testing.  Z Gastroenterol. 1997;  35 609-614
• 32 Ciccocioppo R, Candelli M, Di Francesco D. et al . Study of liver function in healthy elderly subjects using the 13C-methacetin breath test.  Aliment Pharmacol Ther. 2003;  17 271-277
• 33 Lown K S, Kolars J C, Thummel K E. et al . Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test.  Drug Metab Dispos. 1994;  22 947-955
• 34 Lown K S, Bailey D G, Fontana R J. et al . Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.  J Clin Invest. 1997;  99 2545-2553
• 35 Hunt C M, Watkins P B, Saenger P. et al . Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol.  Clin Pharmacol Ther. 1992;  51 18-23
• 36 Hunt C M, Westerkam W R, Stave G M. et al . Hepatic cytochrome P-4503A (CYP3A) activity in the elderly.  Mech Ageing Dev. 1992;  64 189-199
• 37 Watkins P B, Hamilton T A, Annesley T M. et al . The erythromycin breath test as a predictor of cyclosporine blood levels.  Clin Pharmacol Ther. 1990;  48 120-129
• 38 Haas C E, Kaufman D C, Jones C E. et al . Cytochrome P450 3A4 activity after surgical stress.  Crit Care Med. 2003;  31 1338-1346
• 39 Cakaloglu Y, Tredger J M, Devlin J. et al . Importance of cytochrome P-450IIIA activity in determining dosage and blood levels of FK 506 and cyclosporine in liver transplant recipients.  Hepatology. 1994;  20 309-316
• 40 Schmidt L E, Olsen A K, Stentoft K. et al . Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients.  Clin Pharmacol Ther. 2001;  70 446-454
• 41 Branch R A. Drugs as indicators of hepatic function.  Hepatology. 1982;  2 97-105
• 42 Tanaka E, Breimer D D. In vivo function tests of hepatic drug-oxidizing capacity in patients with liver disease.  J Clin Pharm Ther. 1997;  22 237-249
• 43 Willson R A, Hart F E. The comparison of in vivo plasma radioactivity clearance and 14CO2 breath elimination of model drugs in the rat: a study in regional hepatocyte function.  Toxicol Appl Pharmacol. 1981;  61 177-184
• 44 Wietholtz H, Voegelin M, Arnaud M J. et al . Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test.  Eur J Clin Pharmacol. 1981;  21 53-59
• 45 Fontana R J, Turgeon D K, Woolf T F. et al . The caffeine breath test does not identify patients susceptible to tacrine hepatotoxicity.  Hepatology. 1996;  23 1429-1435
• 46 Herold C, Heinz R, Radespiel-Troger M. et al . Quantitative testing of liver function in patients with cirrhosis due to chronic hepatitis C to assess disease severity.  Liver. 2001;  21 26-30
• 47 Caspary W F, Schaffer J. 14C-D-galactose breath test for evaluation of liver function in patients with chronic liver disease.  Digestion. 1978;  17 410-418
• 48 Ishii Y, Asai S, Kohno T. et al . 13CO(2) peak value of L-[1-(13)C]phenylalanine breath test reflects hepatopathy.  J Surg Res. 1999;  86 130-135
• 49 Ishii Y, Asai S, Kohno T. et al . Recovery of liver function in two-third partial hepatectomized rats evaluated by L-[1 - 13C]phenylalanine breath test.  Surgery. 2002;  132 849-856
• 50 Kobayashi T, Kubota K, Imamura H. et al . Hepatic phenylalanine metabolism measured by the [13C]phenylalanine breath test.  Eur J Clin Invest. 2001;  31 356-361
• 51 Burke P A, Stack J A, Wagner D. et al . L-[1-(13)C] Phenylalanine oxida­tion as a measure of hepatocyte functional capacity in end-stage liver disease.  Am J Surg. 1997;  173 270-273
• 52 Tugtekin I, Wachter U, Barth E. et al . Phenylalanine kinetics in healthy volunteers and liver cirrhotics: implications for the phenylalanine breath test.  Am J Physiol Endocrinol Metab. 2002;  283 E1223-E1231
• 53 Epstein C M, Chawla R K, Wadsworth A. et al . Decarboxylation of alpha-ketoisovaleric acid after oral administration in man.  Am J Clin Nutr. 1980;  33 1968-1974
• 54 Michaletz P A, Cap L, Alpert E. et al . Assessment of mitochondrial function in vivo with a breath test utilizing alpha-ketoisocaproic acid.  Hepatology. 1989;  10 829-832
• 55 Bendtsen P, Hannestad U, Pahlsson P. Evaluation of the carbon 13-labeled Ketoisocaproate breath test to assess mitochondrial dysfunction in patients with high alcohol consumption.  Alcohol Clin Exp Res. 1998;  22 1792-1795
• 56 Witschi A, Mossi S, Meyer B. et al . Mitochondrial function reflected by the decarboxylation of [13C]ketoisocaproate is impaired in alcoholics.  Alcohol Clin Exp Res. 1994;  18 951-955
• 57 Honkoop P, de Man R A, Scholte H R. et al . Effect of lamivudine on morphology and function of mitochondria in patients with chronic hepatitis B.  Hepatology. 1997;  26 211-215
• 58 Miele L, Grieco A, Armuzzi A. et al . 13C-Octanoate breath test to assess hepatic mitochondrial beta-oxidation in patients with nonalcoholic steato-hepatitis.  Gut 2000 (Suppl. III): . A134-A135
• 59 Armuzzi A, Zocco M A, Miele L. et al . Assessment of liver mitochondrial beta-oxidation by sodium 13C-Octanoate breath test.  Hepatology. 2000;  32 (Supplement 2) 122
• 60 Ishii Y, Asai S, Kohno T. et al . Evaluation of liver regeneration using the L-[1 - 13C]methionine breath test.  J Surg Res. 2001;  95 195-199
• 61 Armuzzi A, Marcoccia S, Zocco M A. et al . Non-Invasive assessment of human hepatic mitochondrial function through the 13C-methionine breath test.  Scand J Gastroenterol. 2000;  35 650-653
• 62 Caspary W F. Breath-analysis tests in gastroenetrological diagnosis.  Z Gastroenterol. 1975;  13 704-714
• 63 Klein P D. 13C breath tests: visions and realities.  J Nutr. 2001;  131 1637S-1642S