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Letters to the Editor |
Department of Pediatrics, Laboratory Center CMC IV, Room Y2115, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, Netherlands
Dear Sir:
We are grateful for the comments of Murphy et al concerning the metabolic handling of lipids labeled with stable isotopes in relation to our recently published study (1). Murphy et al feel that the conclusions presented in our study are not consistently supported by our own observations, nor by previous observations (2, 3). The reservations of Murphy et al concern an important issue for all studies in which labeled compounds are used, namely, does the metabolic fate of a labeled compound reflect that of the (unlabeled) bulk of this compound? Murphy et al raise 3 issues in this respect: 1) the oxidation of [1-13C]octanoate from 1,3-distearoyl,2[1-13C]octanoyl glycerol ([13C]MTG) in our study, 2) the relation between the plasma concentration of [13C]linoleic acid ([13C]LA) and deficient intestinal fatty acid uptake in our study, and 3) the recovery of 13C-labeled lipids from the feces of control and cystic fibrosis patients in previous studies (2, 3). These 3 aspects will be discussed below in turn.
The [13C]MTG breath test was described originally and validated by Vantrappen et al (4). In healthy subjects and in patients with pancreatic disease, a strong correlation was observed between the 6-h cumulative expiration of 13CO2 and lipase activity in the duodenum after maximal pancreatic stimulation (r = 0.89). Nevertheless, we appreciate the concern of Murphy et al that the oxidation of labeled fatty acids may not be uniform and consistent and may be influenced by nutritional status and metabolic demands. In a previous study, we examined in healthy adults the determinants of the 13CO2 response with the [13C]MTG breath test (5). It appeared that standardization of the test, particularly with respect to physical activity, was warranted. Because the [13C]MTG breath test was used under these standardized conditions in our study, which were virtually identical to the conditions originally described by Vantrappen et al, we do not believe that differences in oxidation rates per se significantly affected our main conclusions.
After their intestinal absorption, medium-chain fatty acids, such as octanoate, are transported in plasma predominantly bound to albumin, are rapidly cleared from plasma, and are subsequently readily oxidized. The postabsorptive metabolism of long-chain fatty acids, such as linoleate and palmitate, is significantly different from that of medium-chain fatty acids, includes the assembly into lipoproteins, and is much less characterized by oxidation. To obtain information on the intestinal absorption of long-chain fatty acids, we developed stable-isotope methods that do not depend on the eventual oxidation of absorbed tracer compounds, but rather on the appearance of the label in an earlier metabolic compartment, ie, the plasma. In permanently bile-diverted rats, an accepted animal model for impaired long-chain fatty acid solubilization, plasma concentrations of [13C]LA between 1 and 4 h after its enteral administration were closely related to the efficacy of gross fat absorption and to fecal fat excretion (r = 0.84) (6). We agree with Murphy et al that the specificity of such tests of long-chain fatty acid absorption is demonstrated by the independence of the results from pancreatic insufficiency. We showed recently that postabsorptive plasma concentrations of enterally administered [13C]palmitate, another stable, isotopically labeled long-chain fatty acid, were virtually identical in control rats and in rats treated with the intestinal lipase inhibitor orlistat; these rats absorbed only 32.8 ± 3.7% of ingested dietary fats (7). These observations indicate that postabsorptive plasma concentrations of enterally administered, 13C-labeled long-chain fatty acids are specifically and significantly related to the efficacy of their intestinal solubilization and uptake. Although we agree with Murphy et al that the removal of labeled fatty acids from the circulation may interfere, present data indicate that, at least in the time scales and fat absorption models studied so far (bile-diverted rats, orlistat-treated rats, pediatric cystic fibrosis patients) (1, 6, 7), their relative contribution to 13C-labeled plasma concentrations appears to be minor.
On the basis of previous studies by Murphy et al, it is apparent that the recovery of [13C] label in feces is not, or is only poorly, related to gross fecal fat excretion after enteral administration of trace amounts of stable isotopically labeled long-chain fatty acids (2, 3, 8). In our own studies, including our recently published study in this Journal, we confirmed their original observation: the 48- or 72-h recovery of 13C label in feces or in fecal fats does not reliably reflect the fate of unlabeled, gross amount of dietary fats (1, 6, 7). The reason for this apparent discrepancy may be related to the administration of a tracer lipid in a physicochemical form that differs from the matrix of unlabeled dietary fats. In addition, the small intestine has a considerable compensatory capacity to uphold quantitative fat absorption under widely variable conditions. For example, when there is impaired fat absorption from the proximal part of the intestine, where the predominant fraction of dietary fats is absorbed under physiologic conditions, the more distal sections of the small intestine may become recruited in fat absorption (9, 10). In our recently published study, however, we found a close correlation between the 8-h plasma concentration of [13C]LA and the net, 72-h absorption of dietary fats (r = 0.88). On the basis of this and previous observations, we are confident that appearance of labeled fatty acids in the plasma compartment, within hours after its administration, more closely reflects rate-limiting steps in malabsorption of dietary fats when compared with the fraction of the tracer fatty acid that, after passage through the whole intestine, remains unabsorbed.
In our opinion, the recently obtained data strongly support the concept that incomplete intraluminal solubilization of long-chain fatty acids, their reduced mucosal uptake, or both processes together impair the absorption of dietary fats in pediatric cystic fibrosis patients (1). We do agree with Murphy et al that the application of stable-isotope tracers in biomedical investigations warrants a critical appraisal with respect to whether the metabolism of the tracer accurately reflects the physiologic process under study.
REFERENCES
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