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Age-dependent alterations of intestinal absorption. II. A clinical study using a modified d -xylose absorption test
Arch. Gerontol. Geriatr., 3 (1984) 97-108 Elsevier
97
AGG 00064
Age-dependent alterations of intestinal absorption. II. A clinical study using a modified D-xylose absorption test * R u d o l f W e i n e r 1, F r i e d h e l m Dietze 2 a n d R e i n h a r d L a u e 3 I St. Georg District Hospital, 7021 Leipzig, 2 Theodor Brugsch Clinic for Internal Diseases, Department of Medicine (Charitb Hospital), Humboldt University, 1040 Berlin, "~Institute of Biophysics, Karl Marx University, 7010 Leipzig, G.D.R.
(Received 26 May 1983; revised version received 10 February 1984; accepted 14 February 1984)
Summary With advancing age functional and morphological changes take place within the intestinal tract. The age-dependency of intestinal absorption has been studied using a D-xylose absorption test. The absorption rate (constant k12), the time of appearance of the relative maximum of the D-xylose concentrations in the blood serum after oral administration (time t,,), and the extent of the relative absorption in the small intestine as a function of time RA(t) were determined by graphic-mathematical evaluation of the blood level kinetics of D-xylose after oral and intravenous administration. Within the age range of 3 to 96 yr, it has been proven that a slowing down of intestinal absorption occurs with advancing age. By prolonging the period during which the food components are absorbed in the small intestine (shift of t m towards later times) the old organism is just as capable of complete absorption as is the young one, even though the absorption processes take place at a slower rate. Absorption disorders in old age are due to morbidity and not, sui generis, to involution. ageing; intestinal absorption; D-xylose test; kinetic parameters
Introduction The absorptive properties of the small intestine - like most biological properties o f o t h e r m u l t i - c e l l u l a r s y s t e m s - a r e s u b j e c t t o m o r e o r less p r o n o u n c e d c h a n g e s w i t h age. I n t h i s p r o c e s s t h e c h a n g e s o f m o r p h o l o g i c a l a n d f u n c t i o n a l f e a t u r e s a r e particularly marked both during the period of development and the period of involution due to ageing. For clinical diagnostics, the problem of differentiating b e t w e e n m o r b i d a n d i n v o l u t i o n a l c h a n g e s i n t h e f u n c t i o n s o f v a r i o u s o r g a n s h a s as * This study was carried out in connection with the Gerontology Research Project sponsored by the G.D.R. Ministry of Health. 0167-4943/84/$03.00 © 1984 Elsevier Science Publishers B.V.
98 yet remained unsolved in many disciplines of modern medicine. Only by an early detection of morbid conditions and their reliable differentiation from changes with age will the necessary prerequisites be created to make full use in clinical practice of the modern possibilities of adequate prophylaxis, metaphylaxis and therapy. Early detection is of special importance to the elderly, whose regulatory and compensatory faculties are limited, in preventing premature death from causes 'related to ageing'. Life is limited not so much by changes with age in vital organic functions as by morbid conditions. With advancing age the disposition to illness is gaining more and more importance. Therefore, it should be the task of preventive geriatrics to detect, at the earliest possible time, any changes in age that represent risk factors. For this purpose it will be necessary to develop further and improve suitable function tests and methods for an early detection and to take appropriate preventive measures. To date it has been an unsolved diagnostic problem to develop a comprehensive function test in order to analyze the absorption in the small intestine. Based on a biophysical model of the absorptive system Laue and Dietze (1976) inaugurated a modified o-xylose test which is well suited to comprehensively assess the process of intestinal absorption. Thus, the prerequisites were created to enlarge the knowledge of age-dependent changes in the intestinal tract. Previous studies on the age-dependency of absorption had produced contradictory results and prevented an assessment of intestinal absorption kinetics. The prospective use of the modified o-xylose test within the age range of 3 to 96 yr is to comprehensively analyze the age-dependent changes taking place in the process of intestinal absorption.
Material and Methods
The modified D-xylose absorption test was used on 162 subjects (92 females, 70 males) aged 3 to 96 yr. The age distribution can be seen in Fig. 1 and Table I. None of the subjects under study had a digestive disease or known cancer at the time of the investigation, and none was under pharmacotherapy, the influence of which on the process of absorption is well-known. Only 7 of the 66 patients over 50 yr were on 30 ['1.3 m
40
"20
30 2O
"10
!
3 age I'years3
Fig. 1, Absolute and relative (~) frequency distribution of age among the patients from 3 to 96 yr (n = 162), class interval: 18.6 yr.
79 67.9 14.7 46.0 96.0 66.3 1.7
83
21.1 12.9 3.0 44.0 16.5 1.4
Number Arithmetic mean of age Standard deviation Minimum value Maximum value Geometrical mean Standard error
1.2
1.1
Group
6.2 2.0 3.0 9.0 5.8 0.4
22
2.1
13.4 2.7 10.0 19.0 13.2 0.6
19
2.2
Statistical dimension figures of grouping; parameter: age (yr).
TABLE I
24.7 2.9 20.0 29.0 24.5 0.7
16
2.3
35.5 2.5 30.0 39.0 35.4 0.6
20
2.4
45.8 2.8 40.0 49.0 45.8 0.7
18
2.5
53.8 2.9 50.0 59.0 53.7 0.8
13
2.6
64.5 3.0 60.0 69.0 64.4 0.7
17
2.7
73.9 2.9 70.0 79.0 73.8 0.7
18
2.8
83.3 3.2 80.0 89.0 83.2 1.0
11
2.9
93.9 2.5 90.0 96.0 93.8 0.9
8
2.10
100 cardiac glycosides. On the day of the investigation these patients were given the glycoside after the function test was completed. Diabetics were not included. For the purpose of a detailed data analysis the following grouping was done (Table I): Grouping 1 Since the average age of all patients included in the study was 43.91 yr, the differentiating age of 44 yr was taken as the basis to form two groups of comparable size (Group 1 . 1 : 3 - 4 4 yr; Group 1.2:45-96 yr). Grouping 2 The subdivision of the patients according to decades (Group 2 . 1 : 3 - 9 yr; Group 2 . 2 : 1 0 - 1 9 yr; Group 2 . 3 : 2 0 - 2 9 yr; Group 2 . 4 : 3 0 - 3 9 yr; Group 2.5: 40-49 yr; . . . G r o u p 2.10:90-96 yr) serves to analyze the kinetics of the process of absorption in different periods of life.
Methods The principle of the modified D-xylose absorption test is based on the oral and intravenous administration of 10 g of D-xylose and the subsequent graphic-mathematical evaluation of blood-xylose kinetics (the theoretical foundations of this test have been described in detail by Laue et al. (1984 - see previous paper)). The clinical investigation program The oral and intravenous administration of xylose is performed separately at an interval of at least 12 h. The oral D-xylose application is done on an empty stomach (after fasting for at least 6 h). After collection of a venous fasting blood sample ' N ' (amount: 5 ml) the subject is given orally a test dose of 10 g of D-xylose dissolved in 150 ml of tea. This draught is taken within no more than 2 min. Thereafter, blood samples (amount: 5 ml) are collected at fixed times t = 15, 30, 45, 120, 150 and 180 min after the draught was finished from an in-dwelling venule. The time is measured as from the moment the subject finishes the test draught (t = 0). During the test the subject is not confined to bed. The intravenous application of 10 g of D-xylose is done in the form of a 10% sterile and pyrogen-free D-xylose infusion solution. The time of application should not exceed 7 rain. After collection of a fasting blood sample ' N ' (amount: 5 ml) 100 ml of a 10% D-xylose infusion solution are applied using the single-slope technique. Again, blood samples are taken at fixed times t = 60, 120 and 180 min after completion of the intravenous D-xylose application. After the investigation has been completed the blood samples are subjected to a chemical laboratory analysis to have their D-xylose content determined. In children up to 14 yr of age capillary blood (0.1 ml) is collected and the D-xylose concentration determined by a micromethod. The chemical identification of D-xylose in the blood serum or plasma In determining the D-xylose concentration in the blood serum or plasma the 4-bromaniline method (Roe and Rice, 1948) has proved most effective. The variation coefficient of the individual values is 4.2% (Weiner et al., 1978). The graphic-mathematical evaluation The D-xylose concentrations in the blood serum or plasma as determined after the
101 oral and intravenous administration of 10 g of D-xylose, in principle, can be evaluated in two ways.
The graphic-mathematical evaluation (manual method) The advantage of this method lies in the immediate determination of the test result. It is easy to apply and requires little time. The following steps have to be taken in the given order: the D-xylose serum concentrations are plotted on a semilogarithmic coordinate system (Figs. 2 and 4). From the values on the descending part of the curve of the D-xylose concentrations in the blood serum after oral administration of the test dose a straight line (I) can be constructed in accordance with Gauss' minimal principle (Fig. 2). The slope of this straight line as determined according to the principle of biological half-life characterizes the elimination function (constant K2) for D-xylose from the organism. The values on the ascending part of the curve, i.e. those obtained before the relative maximum (tm) is reached, are subtracted from the instantaneous values of the straight line I which go with them. The auxiliary points thus obtained are plotted on the coordinate system (Fig. 3), and a second straight line (II) is constructed. The slope of this straight line characterizes the rate of intestinal absorption (absorption constant k12 ). The point of intersection of the straight line I with the ordinate is read off as the dose-dependent constant D. The values measured after the intravenous administration of 10 g of D-xylose decrease exponentially as a function of time. From their numerical magnitudes a straight line is constructed (Fig. 4). The slope of this straight line characterizes the elimination function for D-xylose (elimination constant k 0). The constants k 0 and K 2 are not identical. The point of intersection of the straight line with the ordinate characterizes the dose-dependent constant A. The parameters A, D, k12 , K 2 and k o C (m91100 ml ) 100-
SO.
D,,l.,,.o 20-
10.
Ij
O - ~(mtlllgO ml )
o.m
o,.]
I
K~- ~-'1 -rm-~
s-
I
K2- O,OO&TI (rni~ I )
J
I I 1
,
,
J tl ,
.
~ t2 i
®
. . . . . . . . . .
1~
rain
1;o
Fig. 2. Principle of the graphic evaluation of the D-xylose concentrations in the blood serum after the oral application of the test substance (Step 1).
102 c (mltw0na)
D
~
JI s~l i
x°
,~.~_u.um t2-h ~2
I\ I ~
i I '""
~ "°~c~4)
Fig. 3. Principle of the graphic evaluation of the D-xylose concentrations in the blood serum after the oral application of the test substance (Step 2).
as determined in the graphic-computational manner described above are inserted in Equation 1, and the effective absorption can be calculated up to any time t. RA(%) =
lO0"D'(k12-k°)-(1-e
-k'2')
.4 .k12
+
100. D . ( k 0 - r 2 ) "(1 A •K 2
e -K2')
(1)
If one wants to determine the effective absorption in different ranges of age, it is recommendable to use an age-independent time for assessing the absorption function. This time is identical with the moment at which the relative m a x i m u m of the D-xylose concentration in the blood serum after.oral administration of D-xylose is reached. Its numerical magnitude can be calculated (Equation 2). Thus, by determining generalized absorption until the time I m is reached a differentiation can be made between morbid and involutional changes in intestinal absorption. tm
2.30 k12 k ] 2 - K 2 "lgr 2-
(2)
Computerprogram Larger data quantities can be processed with the help of a computer program (Karsten et al., 1982). After the data have been fed into the computer the most important absorption parameters will be printed out for the user. In our clinical routine diagnostics, where the result of the function test is decisive for the further
103 diagnostic and therapeutic strategy, the data obtained are evaluated immediately by hand.
Results and Discussion
The rate of absorption in the process of ageing According to the description of the biophysical model (Laue and Dietze, 1976) intestinal absorption is characterized as a generalized shift (shift in mass) R(t) between the compartments N1 (lumen of the small intestine) and N2 (blood plasma). The fact that the temporal behaviour of the shift in mass (absorption) depends on the parameter k12 only justifies the designation 'constant of absorption'. Therefore, its alteration in the process of ageing is of importance when it comes to answering the question as to whether or not there are any changes with age in the process of intestinal absorption. As a result of the experimental clinical investigations a statistically significant decrease in the numerical magnitude of the constant k12 within the age range of 3 to 96 yr can be shown to occur with advancing age. This process can be described by a regression function of first order (Table II, Fig. 5). When subdividing the material into two groups of comparable size with the differentiating age of 45 yr, these dynamic changes in the process of absorption can also be described by statistically significant regression functions (Table III). However, in the age group comprising the patients from 3 to 44 yr the coefficients of determination are lower than in the group of older patients. Hence, in the group of patients over 45 yr the decrease of the numerical magnitude k~2 and thus the slowing
c (me~tOo m4)
100-
i~
(rngllO0ml)
2O " m r . . . . . .
I• lo-
s
O,Eg3 O,EQ3
, ~'tr-:
~
I
~" " ~-~
I "0,00912(min"11
II
I I I I It
I I I I It 60
mln
120
lml
Fig. 4. Principle of the graphic evaluation of the D-xylose concentrations in the blood serum after the intravenous application of the test substance.
104 TABLE II Regression function for the rate of absorption (constant k12 ) as a function of age ( P < 0.05). Age range: 3-96 yr (n = 162) kl2 ( m i n - 1) = 0.047269 - 0.0002789. a (yr) Coefficient of determination: 48.09% Residual variation: 0.79088.10 -2
down of the process of absorption are determined to a far greater extent by the factor 'age' than they are in younger patients.
The appearance of the relative maximum t,, of the D-xylose concentrations in the blood serum after oral application as a function of age The fact that k12 decreases with advancing age within the age range of 3 to 96 yr is of practical importance, for this decrease leads to a temporal shift of the relative maximum t m as a result of which the latter appears at later times (regression function of second order, Table IV, Fig. 6). Hence, this parameter t m has the greatest age specificity and as such is best suited to characterize the involutional changes taking place in the process of intestinal absorption. With the tin-value a state is reached in the process of absorption which is comparable for all ages. This state is characterized by an equilibrium between the extent of intestinal absorption and the extent of elimination, while at those times where t > tm, i.e. beyond the relative maximum, elimination will more and more exceed absorption. In fact, the process of
k,2[min-~ 0.07-
1(,
1( 2
o
~
~ age
,
100
ryeam.3
Fig. 5. Dependency of the intestinal absorption rate constant k12 ( r a i n - t ) on age (years), linear regression function; age range: 3-96 yr, ~ : upper limit, K2: lower limit of the confidence interval.
105
TABLE Ill Regression function for the rate of absorption (constant kl2 ) as a function of age ( P < 0.05). Group 1.1 Age range: 3-44 yr (n = 83) k12 ( m i n - 1) = 0.046356 - 0.00023256- a (yr) Coefficient of determination: 14.35% Residual variation: 0.73483.10 -2 Group 1.2 Age range: 45-96 yr (n = 79) kl2 (rain- 1) = 0.035519 - 0.20303.10- 7. a 3 (yr) Coefficient of determination: 22.61% Residual variation: 0.0084682
TABLE IV Regression function for the appearance in terms of time of the relative maximum of the D-xylose concentrations in the blood serum after oral pentose application (time t m) as a function of age ( P < 0.05). Age range: 3-96 yr (n = 162) t m ( m i n ) = 49.649+0.0062917. a 2 (yr) Coefficient of determination: 61.12% Residual variation: 0.13024-102
absorption will actually come to an end at a certain point of time t > tm, namely when the substrate available for absorption has left the absorptive sections of the small intestine. However, this point of time can neither experimentally nor theoretically be determined by our methods of investigation. All that can be said with certainty as regards the limitation in terms of time of the process of absorption applies to the time t m. As has been confirmed by our investigations, the bulk of the total amount that is finally absorbed will always be taken up by the time the relative
to
[:io]
150-
100" X~ 50. X2
o,
6
~
16o
age Fyears3
Fig. 6. Dependency of the appearance of t m on age (yr), regression function of second order, age range: 3-96 yr, rl: upper limit, •2: lower limit of the confidence interval,
106 maximum t m is reached. The clear dependence on age of the appearance of the relative maximum t m can be established statistically by regression analyses in the two age groups 1.1 (3-44 yr) and 1.2 (45-96 yr) (Table V). Since t m represents, in the process of absorption, a characteristic parameter depending explicitly on age it lends itself to assessing, by way of comparison, the extent of intestinal absorption in the process of ageing.
The extent of absorption in the small intestine (method of generalized absorption) as a function of age Up to the time the relative maximum t m i s reached the extent of absorption in the small intestine remains almost constant in all age ranges. Until this characteristic time t m an average of 66.13% of the applied D-xylose will be absorbed by all patients, the normal range for the individual values varying between 59.8 and 72.5% ( P <0.001). As could be shown by a statistical comparison of all parameters involved in the process of absorption, including the extent of absorption at defined times t (t t = 30 min, t 2 = 60 min, t 3 = 90 min, t4 = 120 min, t 5 -- 150 min, t 6 = 180 min, tin), it is only the extent of absorption at the time t m (designation: RA(tm) ) that exhibits no significant dependence on the factor age ( P < 0.050) within the age range of 3 to 96 yr. In contrast, the absorption quantities RA(t i ) show with advancing age a statistically significant numerical decrease which can be described by regression functions (Weiner, 1981). This is clearly illustrated by a comparison of the time curves of generalized absorption for the group of the youngest (Group 4.1:3 to 9 yr) and the group of the oldest subjects under study (Group 4.10:90 to 96 yr) (Fig. 7). Although the time curve of generalized absorption for the subjects over 90 yr lies clearly below that for the 3- to 9-yr-old children, almost the same percentage of applied D-xylose is absorbed in both age groups by the time t m (64.6 and 63.6%, respectively). When compared at any given times t i absorption in the small intestine of the elderly is always markedly reduced as against that of younger people. This explains the inadequacy of the function tests used so far in providing an answer to the question whether or not absorption in the small intestine is age-dependent, and if so, to what an extent. Both the slowing down and prolongation of the process of TABLE V Regression functions for the appearance in terms of time of the relative ma xi mum of the D-xylose concentrations in the blood serum after oral pentose application (time t m) as a function of age ( P < 0.05). Gro up 1.1 Age range: 3 - 4 4 yr (n = 83) t m (rain) = 42.422 + 0.51696- a (yr) Coefficient of determination: 36.79~ Residual variation: 8.7641 Gro up 1.2 Age range: 45-96 yr (n = 79) t m (min) = 64.925 + 0.55503.10- 6. a 4 (yr) Coefficient of determination: 39.37~ Residual variation: 15.577
107
RA [o/.] I00
-
t~
tM
{f
f
RR I tm) =
50
I
/
/
R
• 3-11 ogo.~
Jahrt
00
60
120
18O
t Cmi,] Fig. 7. Extent of absorption in the small intestine (generalized absorption) RA(%) as a function of the time t after application of 10 g of o-xylose for the age groups 4.1 (3-9 yr) and 4.10 (90-96 yr) (arithmetic means and standard errors).
absorption with age enable an unlimited intestinal uptake of the ingested food components. This implies that life is not decisively limited by hypokinesia such as is found for many organ functions in old age. All in all, the processes of ageing taking place in the intestinal tract do not lead to any limiting reduction of food utilization. The fact that healthy elderly people do not develop nutritive decompensation, despite the complex possibilities of indigestion there are, can be explained by the longer availability for digestion and absorption of the ingesta (Varga, 1976) due to a reduced gastric and intestinal motility and hence to a reduced rate of passage. In fact, indications of insufficient food utilization are found only seldom in old people, despite limiting influences on the digestive and absorptive capacities. No evidence has as yet been found of an incomplete absorption in advanced age of proteins, carbohydrates, fats, elementary mineral substances as well as water- and fat-soluble vitamins and drugs. The fact that the elderly are often overweight speaks against malabsorption as caused by old age (Ries, 1963). However, if absorption and digestion of an old person are impaired his nutrition will be decisively affected as a result of his reduced adaptability. This explains why in advanced age not only a higher incidence of false nutrition, but also a greater variety of the forms of malnutrition (Windsor, 1979) are observed. In the presence of diseases associated with an obstruction of the passage of the ingesta malabsorption soon develops that can no longer be compensated for by the small intestine, limited as it is in its adaptability. However, such disturbances of intestinal absorption are due to morbidity and not, sui generis, to involution.
108
References Karstens, M. et al. (1982): Service-Programm als Hilfestellung f~r die Diagnostik von Resorptionsst6rungen. In: Probleme der Informatik in Medizin und Biologie, pp. 181-183. Akademie Verlag, Berlin. Laue, R. and F. Dietze (1976): Enterale Resorption. Johann Ambrosius Barth, Leipzig. Laue, R., F. Dietze and Weiner, R. (1984): Age-dependent alterations of intestinal absorption. I. Theoretical aspects. Arch. Gerontol. Geriatr., 3, 87-95. Ries, W. (1963): Das K6rpergewicht unter Beriicksichtigung von Alter und Geschlecht. Z. Alternsforsch., 17, 27-34. Roe, H.J. and Rice, E.W. (1948): A photometric method for determination of free pentoses in animal tissue. J. Biol. Chem., 173, 507-512. Varga, F. (1976): Transit time changes with age in the gastrointestinal tract of the rat. Digestion, 14, 319-324. Weiner, R. (1981): Experimentelle Untersuchungen zur Kinetik von involutiv und morbiditAr bedingten Ver~nderungen der enteralen Resorption. Dissertation B, Berlin. Weiner, R. et al. (1978): Die Ermittlung der generalisierten Resorption im Rahmen des modifizierten D-Xylose-Resorptionstests. Z. Med. Labor-Diagn., 33, 212-217. Windsor, A.C.M. (1979): Nutrition in the elderly. Practitioner, 222, 625-629.
97
AGG 00064
Age-dependent alterations of intestinal absorption. II. A clinical study using a modified D-xylose absorption test * R u d o l f W e i n e r 1, F r i e d h e l m Dietze 2 a n d R e i n h a r d L a u e 3 I St. Georg District Hospital, 7021 Leipzig, 2 Theodor Brugsch Clinic for Internal Diseases, Department of Medicine (Charitb Hospital), Humboldt University, 1040 Berlin, "~Institute of Biophysics, Karl Marx University, 7010 Leipzig, G.D.R.
(Received 26 May 1983; revised version received 10 February 1984; accepted 14 February 1984)
Summary With advancing age functional and morphological changes take place within the intestinal tract. The age-dependency of intestinal absorption has been studied using a D-xylose absorption test. The absorption rate (constant k12), the time of appearance of the relative maximum of the D-xylose concentrations in the blood serum after oral administration (time t,,), and the extent of the relative absorption in the small intestine as a function of time RA(t) were determined by graphic-mathematical evaluation of the blood level kinetics of D-xylose after oral and intravenous administration. Within the age range of 3 to 96 yr, it has been proven that a slowing down of intestinal absorption occurs with advancing age. By prolonging the period during which the food components are absorbed in the small intestine (shift of t m towards later times) the old organism is just as capable of complete absorption as is the young one, even though the absorption processes take place at a slower rate. Absorption disorders in old age are due to morbidity and not, sui generis, to involution. ageing; intestinal absorption; D-xylose test; kinetic parameters
Introduction The absorptive properties of the small intestine - like most biological properties o f o t h e r m u l t i - c e l l u l a r s y s t e m s - a r e s u b j e c t t o m o r e o r less p r o n o u n c e d c h a n g e s w i t h age. I n t h i s p r o c e s s t h e c h a n g e s o f m o r p h o l o g i c a l a n d f u n c t i o n a l f e a t u r e s a r e particularly marked both during the period of development and the period of involution due to ageing. For clinical diagnostics, the problem of differentiating b e t w e e n m o r b i d a n d i n v o l u t i o n a l c h a n g e s i n t h e f u n c t i o n s o f v a r i o u s o r g a n s h a s as * This study was carried out in connection with the Gerontology Research Project sponsored by the G.D.R. Ministry of Health. 0167-4943/84/$03.00 © 1984 Elsevier Science Publishers B.V.
98 yet remained unsolved in many disciplines of modern medicine. Only by an early detection of morbid conditions and their reliable differentiation from changes with age will the necessary prerequisites be created to make full use in clinical practice of the modern possibilities of adequate prophylaxis, metaphylaxis and therapy. Early detection is of special importance to the elderly, whose regulatory and compensatory faculties are limited, in preventing premature death from causes 'related to ageing'. Life is limited not so much by changes with age in vital organic functions as by morbid conditions. With advancing age the disposition to illness is gaining more and more importance. Therefore, it should be the task of preventive geriatrics to detect, at the earliest possible time, any changes in age that represent risk factors. For this purpose it will be necessary to develop further and improve suitable function tests and methods for an early detection and to take appropriate preventive measures. To date it has been an unsolved diagnostic problem to develop a comprehensive function test in order to analyze the absorption in the small intestine. Based on a biophysical model of the absorptive system Laue and Dietze (1976) inaugurated a modified o-xylose test which is well suited to comprehensively assess the process of intestinal absorption. Thus, the prerequisites were created to enlarge the knowledge of age-dependent changes in the intestinal tract. Previous studies on the age-dependency of absorption had produced contradictory results and prevented an assessment of intestinal absorption kinetics. The prospective use of the modified o-xylose test within the age range of 3 to 96 yr is to comprehensively analyze the age-dependent changes taking place in the process of intestinal absorption.
Material and Methods
The modified D-xylose absorption test was used on 162 subjects (92 females, 70 males) aged 3 to 96 yr. The age distribution can be seen in Fig. 1 and Table I. None of the subjects under study had a digestive disease or known cancer at the time of the investigation, and none was under pharmacotherapy, the influence of which on the process of absorption is well-known. Only 7 of the 66 patients over 50 yr were on 30 ['1.3 m
40
"20
30 2O
"10
!
3 age I'years3
Fig. 1, Absolute and relative (~) frequency distribution of age among the patients from 3 to 96 yr (n = 162), class interval: 18.6 yr.
79 67.9 14.7 46.0 96.0 66.3 1.7
83
21.1 12.9 3.0 44.0 16.5 1.4
Number Arithmetic mean of age Standard deviation Minimum value Maximum value Geometrical mean Standard error
1.2
1.1
Group
6.2 2.0 3.0 9.0 5.8 0.4
22
2.1
13.4 2.7 10.0 19.0 13.2 0.6
19
2.2
Statistical dimension figures of grouping; parameter: age (yr).
TABLE I
24.7 2.9 20.0 29.0 24.5 0.7
16
2.3
35.5 2.5 30.0 39.0 35.4 0.6
20
2.4
45.8 2.8 40.0 49.0 45.8 0.7
18
2.5
53.8 2.9 50.0 59.0 53.7 0.8
13
2.6
64.5 3.0 60.0 69.0 64.4 0.7
17
2.7
73.9 2.9 70.0 79.0 73.8 0.7
18
2.8
83.3 3.2 80.0 89.0 83.2 1.0
11
2.9
93.9 2.5 90.0 96.0 93.8 0.9
8
2.10
100 cardiac glycosides. On the day of the investigation these patients were given the glycoside after the function test was completed. Diabetics were not included. For the purpose of a detailed data analysis the following grouping was done (Table I): Grouping 1 Since the average age of all patients included in the study was 43.91 yr, the differentiating age of 44 yr was taken as the basis to form two groups of comparable size (Group 1 . 1 : 3 - 4 4 yr; Group 1.2:45-96 yr). Grouping 2 The subdivision of the patients according to decades (Group 2 . 1 : 3 - 9 yr; Group 2 . 2 : 1 0 - 1 9 yr; Group 2 . 3 : 2 0 - 2 9 yr; Group 2 . 4 : 3 0 - 3 9 yr; Group 2.5: 40-49 yr; . . . G r o u p 2.10:90-96 yr) serves to analyze the kinetics of the process of absorption in different periods of life.
Methods The principle of the modified D-xylose absorption test is based on the oral and intravenous administration of 10 g of D-xylose and the subsequent graphic-mathematical evaluation of blood-xylose kinetics (the theoretical foundations of this test have been described in detail by Laue et al. (1984 - see previous paper)). The clinical investigation program The oral and intravenous administration of xylose is performed separately at an interval of at least 12 h. The oral D-xylose application is done on an empty stomach (after fasting for at least 6 h). After collection of a venous fasting blood sample ' N ' (amount: 5 ml) the subject is given orally a test dose of 10 g of D-xylose dissolved in 150 ml of tea. This draught is taken within no more than 2 min. Thereafter, blood samples (amount: 5 ml) are collected at fixed times t = 15, 30, 45, 120, 150 and 180 min after the draught was finished from an in-dwelling venule. The time is measured as from the moment the subject finishes the test draught (t = 0). During the test the subject is not confined to bed. The intravenous application of 10 g of D-xylose is done in the form of a 10% sterile and pyrogen-free D-xylose infusion solution. The time of application should not exceed 7 rain. After collection of a fasting blood sample ' N ' (amount: 5 ml) 100 ml of a 10% D-xylose infusion solution are applied using the single-slope technique. Again, blood samples are taken at fixed times t = 60, 120 and 180 min after completion of the intravenous D-xylose application. After the investigation has been completed the blood samples are subjected to a chemical laboratory analysis to have their D-xylose content determined. In children up to 14 yr of age capillary blood (0.1 ml) is collected and the D-xylose concentration determined by a micromethod. The chemical identification of D-xylose in the blood serum or plasma In determining the D-xylose concentration in the blood serum or plasma the 4-bromaniline method (Roe and Rice, 1948) has proved most effective. The variation coefficient of the individual values is 4.2% (Weiner et al., 1978). The graphic-mathematical evaluation The D-xylose concentrations in the blood serum or plasma as determined after the
101 oral and intravenous administration of 10 g of D-xylose, in principle, can be evaluated in two ways.
The graphic-mathematical evaluation (manual method) The advantage of this method lies in the immediate determination of the test result. It is easy to apply and requires little time. The following steps have to be taken in the given order: the D-xylose serum concentrations are plotted on a semilogarithmic coordinate system (Figs. 2 and 4). From the values on the descending part of the curve of the D-xylose concentrations in the blood serum after oral administration of the test dose a straight line (I) can be constructed in accordance with Gauss' minimal principle (Fig. 2). The slope of this straight line as determined according to the principle of biological half-life characterizes the elimination function (constant K2) for D-xylose from the organism. The values on the ascending part of the curve, i.e. those obtained before the relative maximum (tm) is reached, are subtracted from the instantaneous values of the straight line I which go with them. The auxiliary points thus obtained are plotted on the coordinate system (Fig. 3), and a second straight line (II) is constructed. The slope of this straight line characterizes the rate of intestinal absorption (absorption constant k12 ). The point of intersection of the straight line I with the ordinate is read off as the dose-dependent constant D. The values measured after the intravenous administration of 10 g of D-xylose decrease exponentially as a function of time. From their numerical magnitudes a straight line is constructed (Fig. 4). The slope of this straight line characterizes the elimination function for D-xylose (elimination constant k 0). The constants k 0 and K 2 are not identical. The point of intersection of the straight line with the ordinate characterizes the dose-dependent constant A. The parameters A, D, k12 , K 2 and k o C (m91100 ml ) 100-
SO.
D,,l.,,.o 20-
10.
Ij
O - ~(mtlllgO ml )
o.m
o,.]
I
K~- ~-'1 -rm-~
s-
I
K2- O,OO&TI (rni~ I )
J
I I 1
,
,
J tl ,
.
~ t2 i
®
. . . . . . . . . .
1~
rain
1;o
Fig. 2. Principle of the graphic evaluation of the D-xylose concentrations in the blood serum after the oral application of the test substance (Step 1).
102 c (mltw0na)
D
~
JI s~l i
x°
,~.~_u.um t2-h ~2
I\ I ~
i I '""
~ "°~c~4)
Fig. 3. Principle of the graphic evaluation of the D-xylose concentrations in the blood serum after the oral application of the test substance (Step 2).
as determined in the graphic-computational manner described above are inserted in Equation 1, and the effective absorption can be calculated up to any time t. RA(%) =
lO0"D'(k12-k°)-(1-e
-k'2')
.4 .k12
+
100. D . ( k 0 - r 2 ) "(1 A •K 2
e -K2')
(1)
If one wants to determine the effective absorption in different ranges of age, it is recommendable to use an age-independent time for assessing the absorption function. This time is identical with the moment at which the relative m a x i m u m of the D-xylose concentration in the blood serum after.oral administration of D-xylose is reached. Its numerical magnitude can be calculated (Equation 2). Thus, by determining generalized absorption until the time I m is reached a differentiation can be made between morbid and involutional changes in intestinal absorption. tm
2.30 k12 k ] 2 - K 2 "lgr 2-
(2)
Computerprogram Larger data quantities can be processed with the help of a computer program (Karsten et al., 1982). After the data have been fed into the computer the most important absorption parameters will be printed out for the user. In our clinical routine diagnostics, where the result of the function test is decisive for the further
103 diagnostic and therapeutic strategy, the data obtained are evaluated immediately by hand.
Results and Discussion
The rate of absorption in the process of ageing According to the description of the biophysical model (Laue and Dietze, 1976) intestinal absorption is characterized as a generalized shift (shift in mass) R(t) between the compartments N1 (lumen of the small intestine) and N2 (blood plasma). The fact that the temporal behaviour of the shift in mass (absorption) depends on the parameter k12 only justifies the designation 'constant of absorption'. Therefore, its alteration in the process of ageing is of importance when it comes to answering the question as to whether or not there are any changes with age in the process of intestinal absorption. As a result of the experimental clinical investigations a statistically significant decrease in the numerical magnitude of the constant k12 within the age range of 3 to 96 yr can be shown to occur with advancing age. This process can be described by a regression function of first order (Table II, Fig. 5). When subdividing the material into two groups of comparable size with the differentiating age of 45 yr, these dynamic changes in the process of absorption can also be described by statistically significant regression functions (Table III). However, in the age group comprising the patients from 3 to 44 yr the coefficients of determination are lower than in the group of older patients. Hence, in the group of patients over 45 yr the decrease of the numerical magnitude k~2 and thus the slowing
c (me~tOo m4)
100-
i~
(rngllO0ml)
2O " m r . . . . . .
I• lo-
s
O,Eg3 O,EQ3
, ~'tr-:
~
I
~" " ~-~
I "0,00912(min"11
II
I I I I It
I I I I It 60
mln
120
lml
Fig. 4. Principle of the graphic evaluation of the D-xylose concentrations in the blood serum after the intravenous application of the test substance.
104 TABLE II Regression function for the rate of absorption (constant k12 ) as a function of age ( P < 0.05). Age range: 3-96 yr (n = 162) kl2 ( m i n - 1) = 0.047269 - 0.0002789. a (yr) Coefficient of determination: 48.09% Residual variation: 0.79088.10 -2
down of the process of absorption are determined to a far greater extent by the factor 'age' than they are in younger patients.
The appearance of the relative maximum t,, of the D-xylose concentrations in the blood serum after oral application as a function of age The fact that k12 decreases with advancing age within the age range of 3 to 96 yr is of practical importance, for this decrease leads to a temporal shift of the relative maximum t m as a result of which the latter appears at later times (regression function of second order, Table IV, Fig. 6). Hence, this parameter t m has the greatest age specificity and as such is best suited to characterize the involutional changes taking place in the process of intestinal absorption. With the tin-value a state is reached in the process of absorption which is comparable for all ages. This state is characterized by an equilibrium between the extent of intestinal absorption and the extent of elimination, while at those times where t > tm, i.e. beyond the relative maximum, elimination will more and more exceed absorption. In fact, the process of
k,2[min-~ 0.07-
1(,
1( 2
o
~
~ age
,
100
ryeam.3
Fig. 5. Dependency of the intestinal absorption rate constant k12 ( r a i n - t ) on age (years), linear regression function; age range: 3-96 yr, ~ : upper limit, K2: lower limit of the confidence interval.
105
TABLE Ill Regression function for the rate of absorption (constant kl2 ) as a function of age ( P < 0.05). Group 1.1 Age range: 3-44 yr (n = 83) k12 ( m i n - 1) = 0.046356 - 0.00023256- a (yr) Coefficient of determination: 14.35% Residual variation: 0.73483.10 -2 Group 1.2 Age range: 45-96 yr (n = 79) kl2 (rain- 1) = 0.035519 - 0.20303.10- 7. a 3 (yr) Coefficient of determination: 22.61% Residual variation: 0.0084682
TABLE IV Regression function for the appearance in terms of time of the relative maximum of the D-xylose concentrations in the blood serum after oral pentose application (time t m) as a function of age ( P < 0.05). Age range: 3-96 yr (n = 162) t m ( m i n ) = 49.649+0.0062917. a 2 (yr) Coefficient of determination: 61.12% Residual variation: 0.13024-102
absorption will actually come to an end at a certain point of time t > tm, namely when the substrate available for absorption has left the absorptive sections of the small intestine. However, this point of time can neither experimentally nor theoretically be determined by our methods of investigation. All that can be said with certainty as regards the limitation in terms of time of the process of absorption applies to the time t m. As has been confirmed by our investigations, the bulk of the total amount that is finally absorbed will always be taken up by the time the relative
to
[:io]
150-
100" X~ 50. X2
o,
6
~
16o
age Fyears3
Fig. 6. Dependency of the appearance of t m on age (yr), regression function of second order, age range: 3-96 yr, rl: upper limit, •2: lower limit of the confidence interval,
106 maximum t m is reached. The clear dependence on age of the appearance of the relative maximum t m can be established statistically by regression analyses in the two age groups 1.1 (3-44 yr) and 1.2 (45-96 yr) (Table V). Since t m represents, in the process of absorption, a characteristic parameter depending explicitly on age it lends itself to assessing, by way of comparison, the extent of intestinal absorption in the process of ageing.
The extent of absorption in the small intestine (method of generalized absorption) as a function of age Up to the time the relative maximum t m i s reached the extent of absorption in the small intestine remains almost constant in all age ranges. Until this characteristic time t m an average of 66.13% of the applied D-xylose will be absorbed by all patients, the normal range for the individual values varying between 59.8 and 72.5% ( P <0.001). As could be shown by a statistical comparison of all parameters involved in the process of absorption, including the extent of absorption at defined times t (t t = 30 min, t 2 = 60 min, t 3 = 90 min, t4 = 120 min, t 5 -- 150 min, t 6 = 180 min, tin), it is only the extent of absorption at the time t m (designation: RA(tm) ) that exhibits no significant dependence on the factor age ( P < 0.050) within the age range of 3 to 96 yr. In contrast, the absorption quantities RA(t i ) show with advancing age a statistically significant numerical decrease which can be described by regression functions (Weiner, 1981). This is clearly illustrated by a comparison of the time curves of generalized absorption for the group of the youngest (Group 4.1:3 to 9 yr) and the group of the oldest subjects under study (Group 4.10:90 to 96 yr) (Fig. 7). Although the time curve of generalized absorption for the subjects over 90 yr lies clearly below that for the 3- to 9-yr-old children, almost the same percentage of applied D-xylose is absorbed in both age groups by the time t m (64.6 and 63.6%, respectively). When compared at any given times t i absorption in the small intestine of the elderly is always markedly reduced as against that of younger people. This explains the inadequacy of the function tests used so far in providing an answer to the question whether or not absorption in the small intestine is age-dependent, and if so, to what an extent. Both the slowing down and prolongation of the process of TABLE V Regression functions for the appearance in terms of time of the relative ma xi mum of the D-xylose concentrations in the blood serum after oral pentose application (time t m) as a function of age ( P < 0.05). Gro up 1.1 Age range: 3 - 4 4 yr (n = 83) t m (rain) = 42.422 + 0.51696- a (yr) Coefficient of determination: 36.79~ Residual variation: 8.7641 Gro up 1.2 Age range: 45-96 yr (n = 79) t m (min) = 64.925 + 0.55503.10- 6. a 4 (yr) Coefficient of determination: 39.37~ Residual variation: 15.577
107
RA [o/.] I00
-
t~
tM
{f
f
RR I tm) =
50
I
/
/
R
• 3-11 ogo.~
Jahrt
00
60
120
18O
t Cmi,] Fig. 7. Extent of absorption in the small intestine (generalized absorption) RA(%) as a function of the time t after application of 10 g of o-xylose for the age groups 4.1 (3-9 yr) and 4.10 (90-96 yr) (arithmetic means and standard errors).
absorption with age enable an unlimited intestinal uptake of the ingested food components. This implies that life is not decisively limited by hypokinesia such as is found for many organ functions in old age. All in all, the processes of ageing taking place in the intestinal tract do not lead to any limiting reduction of food utilization. The fact that healthy elderly people do not develop nutritive decompensation, despite the complex possibilities of indigestion there are, can be explained by the longer availability for digestion and absorption of the ingesta (Varga, 1976) due to a reduced gastric and intestinal motility and hence to a reduced rate of passage. In fact, indications of insufficient food utilization are found only seldom in old people, despite limiting influences on the digestive and absorptive capacities. No evidence has as yet been found of an incomplete absorption in advanced age of proteins, carbohydrates, fats, elementary mineral substances as well as water- and fat-soluble vitamins and drugs. The fact that the elderly are often overweight speaks against malabsorption as caused by old age (Ries, 1963). However, if absorption and digestion of an old person are impaired his nutrition will be decisively affected as a result of his reduced adaptability. This explains why in advanced age not only a higher incidence of false nutrition, but also a greater variety of the forms of malnutrition (Windsor, 1979) are observed. In the presence of diseases associated with an obstruction of the passage of the ingesta malabsorption soon develops that can no longer be compensated for by the small intestine, limited as it is in its adaptability. However, such disturbances of intestinal absorption are due to morbidity and not, sui generis, to involution.
108
References Karstens, M. et al. (1982): Service-Programm als Hilfestellung f~r die Diagnostik von Resorptionsst6rungen. In: Probleme der Informatik in Medizin und Biologie, pp. 181-183. Akademie Verlag, Berlin. Laue, R. and F. Dietze (1976): Enterale Resorption. Johann Ambrosius Barth, Leipzig. Laue, R., F. Dietze and Weiner, R. (1984): Age-dependent alterations of intestinal absorption. I. Theoretical aspects. Arch. Gerontol. Geriatr., 3, 87-95. Ries, W. (1963): Das K6rpergewicht unter Beriicksichtigung von Alter und Geschlecht. Z. Alternsforsch., 17, 27-34. Roe, H.J. and Rice, E.W. (1948): A photometric method for determination of free pentoses in animal tissue. J. Biol. Chem., 173, 507-512. Varga, F. (1976): Transit time changes with age in the gastrointestinal tract of the rat. Digestion, 14, 319-324. Weiner, R. (1981): Experimentelle Untersuchungen zur Kinetik von involutiv und morbiditAr bedingten Ver~nderungen der enteralen Resorption. Dissertation B, Berlin. Weiner, R. et al. (1978): Die Ermittlung der generalisierten Resorption im Rahmen des modifizierten D-Xylose-Resorptionstests. Z. Med. Labor-Diagn., 33, 212-217. Windsor, A.C.M. (1979): Nutrition in the elderly. Practitioner, 222, 625-629.