Phenylalanine kinetics in cirrhosis

To the editor: In their recent study, Tugtekin et al. (5) compared whole body phenylalanine (Phe) metabolism in patients with liver cirrhosis and healthy controls. It is assumed that changes in whole body amino acid metabolism in these patients is due to the reduced metabolic capacity of the liver. As an essential amino acid, Phe has two fates in the body, incorporation into protein or conversion to tyrosine (Tyr). The conversion rate of Phe to Tyr (Qpt) was estimated by Tugtekin et al. using an equation originally presented by Thompson et al. (4), which our group recently examined in more detail (2). On the basis of our observations, it is likely that the estimate of Qpt is inaccurate and that the magnitude of the error varies between cirrhosis patients and controls.

The equation to estimate Qpt uses a tracer-based measurement of Phe flux (Phe appearance from protein breakdown) and an estimate of Tyr flux. This latter estimate is based on the assumption that the ratio of Phe and Tyr flux rates should resemble their relative content in body proteins (4). This assumption is likely to be incorrect, or at least inconsistent, because the Phe and Tyr flux rates depend on the individual breakdown rates of many different protein pools throughout the body with differing Phe and Tyr contents. Thompson et al. (4) originally proposed a Tyr-to-Phe ratio of 0.73 based on contents in animal tissues. However, we found a large variation in the measured ratio of Tyr and Phe flux rates, ranging from 0.52 to 0.81, leading to estimate errors for Qpt as great as 50% (2). The mean ratio value measured was 0.64 in healthy people and 0.72 in people with type 1 diabetes, suggesting that disease state may also be important. For this reason, we concluded that Qpt should be measured using both Phe and Tyr tracers whenever possible. The 0.64 ratio of our normal subjects was applied by Tugtekin et al. in their calculations for people with and without cirrhosis.

Why is this important? Although it has been shown that Phe flux rates are altered in patients with cirrhosis (3), the rate of Qpt has not been measured directly. Estimates of Qpt in cirrhosis may not be accurate for the reasons outlined above. Additionally, the authors (5) state in their opening paragraph that Qpt occurs exclusively in the liver, but it has been demonstrated that the kidney also converts Phe to Tyr and releases a large amout of Tyr to the circulation (1). In fact, the calculated rate of Qpt in the kidney appears to be equal to or greater than that of the splanchnic bed, which includes the liver (1). In cirrhosis patients, the rate of Qpt in liver almost certainly declines, but it is possible that Qpt in kidney remains normal or may even increase in response to the higher circulating Phe levels. If this is the case, then the decline in Qpt would be proportionally less than the decline in Phe flux in patients vs. controls. Because the estimate equation essentially assumes that Qpt varies with Phe flux, the use of the estimate equation for Qpt in cirrhosis patients would not be valid. This question could be resolved in a study that measured Qpt in cirrhosis patients by use of both Phe and Tyr tracers.

REFERENCES

  1. Moller N, Meek S, Bigelow M, Andrews J, and Nair KS. The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: a metabolic role of the kidney. Proc Natl Acad Sci USA 97: 1242–1246, 2000.[Abstract/Free Full Text]
  2. Short KR, Meek SE, Moller N, Ekberg K, and Nair KS. Whole body protein kinetics using Phe and Tyr tracers: an evaluation of the accuracy of approximated flux values. Am J Physiol Endocrinol Metab 276: E1194–E1200, 1998.[ISI]
  3. Tessari P, Inchiostro S, Barazzoni R, Zanetti M, Orlando R, Biolo G, Sergi G, Pino A, and Tiengo A. Fasting and postprandial phenylalanine and leucine kinetics in liver cirrhosis. Am J Physiol Endocrinol Metab 267: E140–E149, 1994.[Abstract/Free Full Text]
  4. Thompson GN, Pacy PJ, Merritt H, Ford GC, Read MA, Cheng KN, and Halliday D. Rapid measurement of whole body and forearm protein turnover using a [2H5]phenylalanine model. Am J Physiol Endocrinol Metab 256: E631–E639, 1989.[Abstract/Free Full Text]
  5. 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]
Kevin R. Short

Endocrinology Research Unit Mayo Clinic and Foundation Rochester, MN 55905 short.kevin{at}mayo.edu 10.1152/ajpendo.00045.2003.





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