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Am J Physiol Endocrinol Metab 285: E448, 2003; doi:10.1152/ajpendo.00173.2003
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LETTERS TO THE EDITOR

REPLY

The main aim of our study (2) was to explore the impact of initial Phe tracer distribution processes, Phe turnover, and whole body CO2 production rates on [13C]Phe breath test values. If these factors were considered, the breath test would give an oxidation rate for cirrhotic patients that, compared with healthy controls, was even more reduced than estimates based on a "simplistic" interpretation of 13CO2 production data. There were some open questions, such as varying retention of 13CO2 between cirrhotic patients and healthy volunteers, which could have influenced our final conclusion. Therefore we also looked at the Pheto-Tyr (Phe/Tyr) conversion rate (Qtp), as it does not depend on metabolic 13CO2 binding or release. These results were interpreted as another "indicator for Phe oxidation," and were used to confirm our finding of a potential underestimation for the intergroup difference. We further stated that "any interpretation beyond that is difficult, because the determination of the Phe-to-Tyr conversion is subject to a large measurement error." Hence, we never used Qpt as a "hard number," nor did we state anywhere that this could be done, because it was calculated from assumed Phe/Tyr protein ratios. For readers who might overlook these confines, the letter of Dr. Short may be helpful.

Dr. Short mentions that there is no valid basis for choosing the appropriate Tyr/Phe protein ratio. We used for both groups a Tyr/Phe protein ratio of 0.68. Considering a higher Tyr/Phe protein ratio for cirrhotic patients, i.e., 0.9, would decrease the intergroup difference in the estimated Qpt values. Generally, an underestimation of the Tyr/Phe protein ratio for cirrhotic patients would lead to an underestimation of Qpt, which would be in favor of larger intergroup differences. However, even for the extreme case of a Phe/Tyr ratio of 0.9 in cirrhotic patients, their estimated conversion rates would increase from 0.7 ± 0.3 to 1.0 ± 0.4 µmol · kg-1 · h-1 and would still be much lower than the control values of 3.0 ± 0.4 µmol · kg-1 · h-1.

Indeed, we missed the study of Moller et al. (1), indicating a substantial Phe/Tyr conversion rate in the kidney. How would a conversion in the kidney influence the interpretation of our data? With the assumption of an equal contribution of liver and kidney, the conversion rate results in ~1.5 µmol · kg-1 · h-1 for both organs in healthy volunteers. Patient data regarding the distribution of the Phe/Tyr conversion between liver and kidney are, to our knowledge, still missing. In our case, the whole body Phe/Tyr conversion in cirrhotic patients is lower than the estimated kidney conversion for controls. Because kidney function in our cirrhotic group was not impaired, as based on creatinine concentrations, the renal Phe/Tyr conversion should not be affected. This, however, would imply that Qpt in the liver would be reduced even more. Generally, as soon as we admit some kidney conversion, the estimate for the hepatic conversion decreases. Hence, even if the underlying metabolic processes are more complex than those we considered, our main interpretation of the data remains valid: the observed reduction of the Phe/Tyr conversion confirms the 13CO2-derived reduction of Phe oxidation. It is tempting to speculate that, in cirrhotic patients, part of the Phe/Tyr conversion is taken over by the kidney and that hepatic conversion would be not sufficient to produce some excess Tyr that escapes into the circulation. Dr. Short recommends using more elaborate tracer protocols to obtain a more reliable estimate for the whole body Qpt conversion rate. However, the gain in reliability does not help if we cannot infer hepatic processes from whole body data. One would have to specify organ conversion rates from tracer-to-tracee balances, which require an invasive catheterization of hepatic and kidney veins combined with blood flow measurements.

REFERENCES

  1. Moller N, Meek S, Bigelow M, Andrews J, and Nair KS. The kidney is an important site for the in vivo phenylalanine-totyrosine conversion in adult humans: a metabolic role of the kidney. Proc Natl Acad Sci USA 97: 1242–1246, 2000.[Abstract/Free Full Text]
  2. Tugtekin I, Wachter U, Barth E, Weidenbach H, Wagner DA, Adler G, Georgieff M, Radermacher P, and Vogt JA. Phenylalanine kinetics in healthy volunteers and liver cirrhotics: implications for the phenylalanine breath test. Am J Physiol Endocrinol Metab 283: E1223–E1231, 2002.[Abstract/Free Full Text]
Josef Vogt

Universitätsklinik Ulm Klinik für Anästhesiologie 89070 Ulm, Germany josef.vogt{at}medizin.uni-ulm.de 10.1152/ajpendo.00173.2003





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