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Improved Estimation of the Calcium Content of Total Digestive Secretions

Osteoporosis Research Center (R.P.H.), Creighton University, Omaha, Nebraska 68131; and U.S. Department of Agriculture/Agricultural Research Service (S.A.A.), Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas 77030

Address all correspondence and requests for reprints to: Robert P. Heaney, M.D., Creighton University, 601 North 30th Street, Suite 4841, Omaha, Nebraska 68131. E-mail: rheaney{at}creighton.edu.

	Abstract

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Because endogenous fecal calcium (EFC) excretion plays a larger role in the calcium economy of adults than does actual calcium intake, and because at typical absorption efficiencies EFC is largely determined by endogenous entry of calcium into the gut [total intestinal calcium (TIC)], it is important to be able to quantify TIC when studying the effect of nutrients, drugs, and disease on body calcium handling.

Measured values for EFC, derived from 553 balance studies in middle-aged women (mean age, 48.8 yr), were pooled with 76 values obtained from premenarcheal girls (mean age, 11.2 yr) after adjusting for differences in body size. The aggregate sample provided values for calcium absorption efficiencies spanning a range from under 10% to over 90%. EFC is known to be inversely related to fractional calcium absorption (AbsFx), and the broad range of absorption efficiencies provided by the composite sample allowed derivation of reasonably precise estimates of EFC at 0% and 100% absorption. These were 0.8067 (± 0.0143) mg/cm height·d and 0.1799 (± 0.0310) mg/cm height·d, respectively. At 0% absorption, EFC is identical to the total entry of calcium into the intestine from endogenous sources (secretions plus sloughed mucosa), whereas at 100% absorption, EFC measures only endogenous entry effectively distal to the absorptive surface. The partition described facilitated derivation of a formula to calculate TIC for any paired values of EFC and AbsFx, i.e. TIC = EFC/[0.223 + 0.777 (1 - AbsFx)].

	Introduction

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SUBSTANTIAL QUANTITIES OF calcium enter the intestinal stream every day from endogenous pools in the form of both digestive secretions and sloughed off mucosal tissue (which turns over at a rate of about 20% per day). This quantity of calcium is not directly measurable in intact healthy individuals, but understanding its magnitude and what controls it are important in working out, at a whole-organism level, the details of calcium absorptive performance and the net nutritional gain from diet calcium under varying dietary and disease conditions.

Heaney and Recker (1) previously published estimates of the total content of calcium entering the gut from endogenous sources, based on calcium tracer-augmented balance studies in healthy, middle-aged women. The accuracy of these efforts was necessarily limited by the fact that calcium absorption efficiency tends to be low in nongrowing individuals, and hence the available data were sparse at the high end of the absorption spectrum. Also, generalizability may have been limited by the age range of the original sample.

More recently, Abrams et al. (2) performed studies in early pubertal, premenarcheal girls in whom absorption efficiency tends to be much higher than in middle-aged women. These studies also used tracer-augmented balance methods. Given this methodological similarity, we chose to explore pooling our respective data sets to produce a more accurate estimate of the total entry of calcium into the digestive stream from endogenous sources [i.e. total intestinal calcium (TIC)] than either data set alone would permit.

	Subjects and Methods

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The analytical methods and balance protocols have all been described elsewhere, and the subjects contributing data also have been characterized elsewhere (3, 4). All subjects gave informed consent (and, when appropriate, assent). Studies in participants with disorders of the gastrointestinal (GI) tract or endocrine system and those taking medications that might affect GI function were excluded from this analysis. All protocols had been approved by the respective institutional review boards for human research of Creighton University and Baylor College of Medicine. Fractional calcium absorption (AbsFx) in both data sets was determined by the gold standard, the double-isotope method (5), and endogenous fecal calcium (EFC) by measuring clearance of the iv administered calcium isotope into feces (1). Briefly,

(1)

where Ca*_F = fecal calcium isotope, Ca*_s = serum calcium-specific radioactivity, and t = the time between iv tracer administration and the effective completion of the fecal collection.

For the data analyzed in this report, there were 553 sets of observations from the adult women (average age, 48.8 yr at study) and 76 sets of observations from the premenarcheal girls (average age, 11.2 yr at study).

	Results

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Normalization of analyzed values for EFC excretion

EFC is that portion of the TIC entering the gut from endogenous sources that escapes absorption and is the only component of TIC that is directly measurable (although doing so requires tracer methods) (1). EFC, as has been reported elsewhere (1) and as confirmed in these data sets, is a function of body size (as well as of absorption efficiency and calcium intake). Indeed, it makes sense that the volume of digestive secretions, as well as the mass of the mucosa (and hence the mass sloughed off each day), would be a function of both body size and the total amount of food that the gut processes.

Because the premenarcheal girls had not reached full adult height or weight (and hence would be expected to have smaller gut length and mass), we explored various body size adjustments (height, weight, body mass index, surface area) to harmonize the two data sets. The method that seemed to work best was to express EFC per unit of height. When this is done, the plot of EFC (milligrams per centimeter of height per day) on absorption fraction (Fig. 1) shows that the two data sets effectively superimpose on the same trend line. Separate bivariate models for the two data sets, regressing EFC on AbsFx, showed no significant difference between the respective equation parameters when a height-based normalization was used. Hence, we concluded that it was valid to pool the data sets using height-adjusted values.

View larger version (32K): [in this window] [in a new window]   FIG. 1. Plot of EFC, expressed as milligrams per centimeter of height per day, in 553 studies in middle-aged women (solid circles) and 76 studies in prepubertal girls (open circles). The solid line is the least-squares linear fit through the data, and the dashed lines show the 95% confidence limits.

Figure 1 also shows that the combined data effectively span virtually the entire range of absorption fractions, and hence extrapolations of the regression line to absorption fractions of 0 and 1 (important for subsequent calculations; see below) can be made with considerable confidence. The regression equations for the best-fit line through the pooled data are

(2)

The best estimates for the y-axis intercepts, i.e. absorption fractions of 0 and 1 (±1 SEM), are 0.8067 (± 0.0143) and 0.1799 (± 0.0310), respectively.

Although calcium enters the GI tract at every level from mouth to anus, it is nevertheless useful to dichotomize this entry into two components, i.e. calcium that enters effectively proximal to the absorptive mucosal surfaces, and calcium that enters effectively distal thereto (1). In other words:

(3)

where PIC = the proximal component and DIC = the distal component of intestinal calcium entry. By this definition, PIC is subject to the same absorption probability as ingested calcium, whereas DIC is excreted intact, irrespective of absorptive efficiency. In other words, at zero absorption, all of the TIC is excreted, and hence measured EFC is numerically identical to TIC. In contrast, at 100% absorption, all of the PIC is absorbed, and measured EFC is numerically identical to DIC.

Using this understanding together with the estimates of the y-axis intercepts at AbsFx = 0 and 1.0 from equation 1, we see that DIC = (0.1799/0.8067)*TIC, or 0.223*TIC, i.e. slightly less than one fourth of TIC enters the gut effectively downstream of the absorptive surface. This allows EFC to be expressed in terms of TIC and its components:

(4A)

(4B)

Simplifying and rearranging, we come up with the following equation:

(4C)

When applied separately to the individual values in the two data sets making up the aggregate used for this analysis, the respective mean values for TIC were 0.806 mg/cm·d for the adult women and 0.807 mg/cm·d for the girls (not significant). The virtual identity of these estimates demonstrates the suitability of the height adjustment.

When applied to the data plotted in Fig. 1, equation 4c produces values about 7% lower for TIC than we had previously reported (1). This difference is due in large part to the fact that the prior formula contained a second-power term in the denominator, whereas equation 4c does not. Also, the current estimate of the partition of TIC into proximal and distal components differs somewhat from the prior estimate.

	Discussion

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As the foregoing exposition makes clear, the estimation of TIC from measured EFC depends heavily on the partition of TIC into proximal and distal components. The added data from the premenarcheal girls with generally higher absorption efficiencies helps substantially in determining this partition because it narrows the range of uncertainty for the intercept at 100% absorption efficiency. A possible weakness of the overall approach when calculating individual values for TIC is the necessary assumption that the group partition of proximal and distal components applies equally to each individual. This is not implausible for individuals at or approaching adult body size, because intestinal mass would be expected to vary more or less directly with body size, and the proportion of its parts would tend to be conserved across different body sizes.

One of the reasons it is useful to be able to estimate TIC with accuracy is that EFC is a more powerful determinant of calcium balance in mature adults than is actual diet calcium (6). Given generally inefficient calcium absorption, particularly in adults, EFC is necessarily determined mainly by TIC. Thus, one of the principal mechanistic causes for negative calcium balance is a high value for TIC. As we have reported elsewhere (7), the apparent malabsorption found in celiac sprue is actually a matter of hypersecretion instead, with values for TIC above average normal by a factor of 2x or greater.

Although our primary concern in this communication is with total entry of endogenous calcium into the digestive stream (i.e. TIC), a possible use of the relationship set forth in equation 2 (and depicted in Fig. 1) might be the ability to estimate EFC without the expense and effort involved in suitably timed fecal collections. In brief, knowing absorption fraction and stature, neither of which requires metabolic balance methods, and holding dietary intakes reasonably constant, one could calculate EFC. The spread of the data apparent in Fig. 1 means that individual measurements based on that regression will necessarily carry broad confidence limits (see equation 2, in which the SE of the estimate is 0.156). However, when used to compare EFC values in reasonably sized samples, the calculated means may well prove to have acceptable confidence intervals.

Little is known about the determinants of TIC. In prior studies, TIC did not seem to be influenced by the usual calcium homeostatic indicators, e.g. PTH, serum calcium (8). Instead, it seemed to be more a function of the size of the gut and the food load that the gut must process. In that sense, it is not importantly influenced by the body’s need for calcium, as are absorption efficiency and urinary calcium reabsorption. This latter point is illustrated in this data set by the fact that height-adjusted TIC was the same for both the growing girls and the mature women. In contrast, urinary calcium loss was only half as great as TIC in the girls, who have a high need for calcium (2), whereas in the adult women, the two outputs are of nearly the same magnitude.

We had reported earlier from two different data sets that TIC rises with phosphorus intake (1, 9) (as well as with body size and some measures of total food intake). Those relations remain true for this expanded data set. It may be noted in passing that this may explain why, in experimental animals such as dogs, whose diets typically exhibit relatively high phosphorus densities, EFC excretion is quantitatively a much more important route of loss from the body than is urine calcium (10). In adult humans, in contrast, as already noted, TIC and urine calcium are of approximately equal magnitude.

	Footnotes

 
This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 079112 and the U.S. Department of Agriculture/Agricultural Research Service under Cooperative Agreement no. 58-6250-6-001, the National Institutes of Health (NIH), National Center for Research Resources General Clinical Research for Children Grant no. R00188, and NIH Grant HD 36591.

Abbreviations: AbsFx, Fractional calcium absorption; DIC, distal component of intestinal calcium entry; EFC, endogenous fecal calcium; GI, gastrointestinal; PIC, proximal component of intestinal calcium; TIC, total intestinal calcium.

Received September 23, 2003.

Accepted December 1, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Heaney RP, Recker RR 1994 Determinants of endogenous fecal calcium in healthy women. J Bone Miner Res 9:1621–1627[Medline]
2. Abrams SA, Griffin IJ, Davila P, Liang L, Powledge D 2001 Effects of very low calcium intake on calcium metabolism in pubertal girls. FASEB J 15:A1095
3. Heaney RP, Recker RR, Saville PD 1977 Calcium balance and calcium requirements in middle-aged women. Am J Clin Nutr 30:1603–1611[Abstract/Free Full Text]
4. Abrams SA, Grusak MA, Stuff J, O’Brien KO 1997 Calcium and magnesium balance in 9–14-y-old children. Am J Clin Nutr 66:1172–1177[Abstract/Free Full Text]
5. DeGrazia JA, Ivanovich P, Fellows H, Rich C 1965 A double isotope method for measurement of intestinal absorption of calcium in man. J Lab Clin Med 66:822–829[Medline]
6. Heaney RP Human calcium absorptive performance–a review. In: Burckhardt P, Heaney RP, eds. Nutritional aspects of osteoporosis. Proc International Symposium on Osteoporosis, Lausanne, Switzerland, 1991. Serono Symposia Publication No. 85. New York: Raven Press, pp 115–123
7. Ott SM, Tucci JR, Heaney RP, Marx SJ 1997 Hypocalciuria and abnormalities in mineral and skeletal homeostasis in patients with celiac sprue without intestinal symptoms. Endocrinol Metab 4:201–206
8. Heaney RP, Skillman TG 1964 Secretion and excretion of calcium by the human gastrointestinal tract. J Lab Clin Med 64:29–41[Medline]
9. Heaney RP, Recker RR 1987 Calcium supplements: anion effects. Bone Miner 2:433–439[Medline]
10. Heaney RP, Harris WH, Cockin J, Weinberg EH 1972 Growth hormone: the effect on skeletal renewal in the adult dog, II. Mineral kinetic studies. Calcif Tissue Res 10:14–22[CrossRef][Medline]

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