Liver Function Test - Methacetin Kinetics

Fig. 1 LiMAx-Test.


Most liver diseases initially cause only mild symptoms. Therefore, they are hard to diagnose in early stages. Moreover, patients with end-stage liver disease need accurate prognostic indicators to plan liver transplantation, and they need an early diagnosis whether transplantation was successful.

Liver function tests can be done e.g. by analyzing serum or plasma samples for enzymes or by time dependent analyzing serum or plasma samples for metabolites after injection of liver substrates.

Less cumbersome for patients are the non-invasive 13C-breath tests. One of numerous 13C-breath tests that can provide quantitative information on hepatic dysfunction is the 13C-methacetin breath test (Fig. 1). This LiMAx-Test was developed by AG Stockmann, Workgroup for the Liver (Stockmann et al., 2009)

13C-methacetin is used as substrate and is selectively metabolized within the liver to paracetamol and labeled CO2 (Fig. 2).







Fig. 2 Metabolization of methacetin within the liver.

The labeled CO2 is later exhaled and (time dependent) measured within the breath. The rate of labeled CO2 is represented according the formula:




with 13C/12CPDB = 0.0112372.

A value of 1‰ DOB (Delta over baseline), therefore, means that one molecule 13CO2 more than usually was found within 89,000 molecules CO2.

A problem for the comparison of methacetin/paracetamol-kinetic and measured 13CO2 is the fact that the temporal process of the metabolization of methacetin is not syncing with the 13C-breath test. Therefore, the straight-forward modeling of the reaction and diffusion processes within the blood (Fig. 3) must be completed by a 3- or 4-compartment model of the bicarbonate flux (Fig. 4). Moreover, the measured CO2 ratios are influenced by the metabolic energy consumption. Such energetic load of course influences the gas exchange, but might influence the metabolism of methacetin, too.

Fig. 3 Model of reaction and diffusion processes within blood (Crandall et al., 1981). Fig. 4 Compartment model of bicarbonate flux (Irving et al., 1983).

The scope of this project is to provide a tool to improve the prediction of liver function by the 13C-methacetin breath test. This shall be done by the following:

  1. Generate a combined model for the methacetin metabolism and bicarbonate flux.
  2. Try to identify the related kinetic constants with the help of experimental data.
  3. Try to identify the influence of exercise on methacetin metabolism, and on bicarbonate flux (Fig. 5).
  4. Show the consistence of the kinetic constants, depending on dose of methacetin, exercise.
  5. Detect clearest possible interrelations between methacetin metabolization (i.e. liver function) and time course of CO2 ratios.


Fig. 5 Influence of exercise on washout of breath 13CO2 (Barstow et al., 1990).

Researchers

Prof. Hermann-Georg Holzhütter
Dr. Andrean Goede
Sascha Bulik

in cooperation with Prof. Peter Neuhaus, Martin Stockmann, Johan Friso Lock, Pouria Taheri, Charité - Universitätsmedizin Berlin, AG Stockmann, Workgroup for the Liver

References

Barstow TJ, Cooper DM, Sobel EM, Landaw EM, Epstein S. (1990) Influence of increased metabolic rate on [13C]bicarbonate washout kinetics. Am J Physiol, 259(1 Pt 2):R163-71. [PubMed]

Crandall ED, Bidani A. (1981) Effects of red blood cell HCO3(-)/Cl- exchange kinetics on lung CO2 transfer: theory. J Appl Physiol, 50(2):265-71. [PubMed]

Irving CS, Wong WW, Shulman RJ, Smith EO, Klein PD. (1983) [13C]bicarbonate kinetics in humans: intra- vs. interindividual variations. Am J Physiol., 245(2):R190-202. [PubMed]

Stockmann M, Lock JF, Riecke B, Heyne K, Martus P, Fricke M, Lehmann S, Niehues SM, Schwabe M, Lemke AJ, Neuhaus P. (2009) Prediction of postoperative outcome after hepatectomy with a new bedside test for maximal liver function capacity. Ann Surg., 250(1):119-25. [PubMed]