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Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, and water
Compartmental Body Composition of Cancer Patients by Measurement of Total Body Nitrogen, Potassium, and Water S. H. Cohn, W. Gartenhaus,
A. Sawitsky,
K. J. Ellis, S. Yasumura, Quantitative
nitrogen
measurement
was
measured
was made of body composition by means
determined
of the
prompt
with the use of a whole body counter.
lean tissue were simultaneously inferred.
estimated
by application
with the use of tritium
The prompt
gamma
over prolonged
wasting,
predominantly
activation
the
appear
and whole
did not change
with the normal contrast
consisted
Medical
Upton.
York
Address
reprint
Island
Deparrmeni
in part of
Medical
to
Dr.
S.
Department.
H.
National
Labo-
Energy.
Manuscript
CC‘, 1981 by Grune & Stratton, 0026-0495/81/3003-0003$01.00/0
Inc.
analysis.
techniques
Total
was
and nonmuscle
body water,
represent
determined
a considerable
advance
make possible sequential
studies
of the loss of muscle mass and body fat. Even
of body
fat.
It is the skeletal
muscle
extent, spared. The nonmuscle to increase
in size when
which
is
tissue including
comparison
was made
has
made of body composition in patients with various forms of neoplastic disease. Total body nitrogen is determined with the use of the prompt gamma neutron activation technique, while total body potassium is measured with the use of a whole body counter. The mass and protein content of the muscle compartment and the nonmuscle lean tissue are estimated by application of a technique of compartmental analysis. Total body water, determined simultaneously with the use of a tritium label, provides a measure of lean body mass. From these data. the body fat can be inferred. Baseline data on body composition of age and sex matched individuals which have already been obtained in an earlier study’ provide a basis for comparison and evaluation. The work covered in the present study is part of a larger study of the dynamic changes in total body nitrogen, potassium and water in cancer patients as a function of time and in relation to the loss of body weight. Following this study, the effect of various regimens of hyperalimentation on body composition will be investigated. The assessment of body cell mass of cancer patients, and the effect on it of various nutritional regimens, is of primary importance in developing appropriate management programs for these patients. Thus, the elucidation of the relationships under study should serve to improve the clinical programs of cancer patients. MATERIALS
Cohn,
Brookhaven
Upton, N. Y. 11970.
by DE-AC02-76CH00016
contract NIH-NCIYOI-CP-80207.
potassium
Jewish-Hillside
April 8. 1980.
requests
Laboratory,
Supported
222
Long
Center, New Hyde Park, New York 11042.
Received for publication National
11973:
disease. Total body
body
The loss of total body water was slight in the cancer patients studied.
Research Center, Brookhaven
New
primarily
amounts
system is, to a considerable
EASUREMENTS of changes in body composition which result from chronic wasting diseases are of great importance, both in evaluation of the status of the patient, and in the determination of appropriate patient management regimens. Of particular interest are the relative proportions of body cell mass, fat, and water. The significant changes that occur in body weight of cancer patients are well known. Further, studies have revealed a decrease in both total body potassium (TBK) and total body nitrogen (TBN) in these patients, associated with this loss of tissue.‘*2 However, the detailed nature of the relationship between the deficits of these two elements is not known. Until very recently, indirect measurement of body composition has been the chief source of data.’ Presently, however, some indirect measurements made by means of balance studies or radioisotopic studies, can be replaced with direct measurements by the application of the nuclear techniques of neutron activation and whole body gamma spectrometry. These latter measurements have both enlarged and refined the data base for the quantification of body compartments. In the present study, quantitative measurement is
From the Medical
body counting
significant
M
ratory,
total
of lean body mass. From these data, the body fat can be
in this study, and actually appeared
population.
technique;
degree of accuracy.
to retain
lost: the visceral life-supporting
the visceral fraction
activation
of compartmental
a measure
by patients with solid tumors
patients
neutron
used in earlier studies. The new techniques
periods of time with a considerable
The loss of body weight in severe
in patients with several forms of neoplastic
gamma
of the technique
techniques
and D. Vartsky
The mass and protein content of the muscle compartment
label, provided
neutron
over the balance and radioisotope
K. Rai, I. Zanzi, A. Vaswani,
E. Cortes,
with
the U.S.
been authored
under
AND
METHODS
Instrumentation The prompt gamma neutron activation facility measures total body nitrogen (TBN) with an accuracy and precision of *3% in the anthropomorphic phantom utilized.3 A detailed description of the prompt gamma neutron activation technique, 14N(n, y)“N, for the absolute measurement of whole body nitrogen has been presented.’ The detector geometry yields a quite uniform composite sensitiv-
Metabolism,
Vol. 30, No. 3 (March), 1981
BODY
COMPOSITION
ity (i.e., an equal
OF CANCER
number
223
PATIENTS
of counts
per unit mass of nitrogen
per
unit dose). The use of an internal standard based on body hydrogen further increases the uniform composite sensitivity and hence increases the accuracy of the measurement4 The present method of nitrogen measurement is reasonably comfortable. It requires only that the patient be scanned both in the prone and supine positions. With the use of restricted beam size and good collimation, the clinician or nurse may remain near the subject during the irradiation. The total radiation time is less than 20 min. and the dose equivalent delivered to the skin in this procedure is 26 mrem. A Quality Factor (QF) of 10 is assumed. The dose equivalent to the bone marrow is approximately one-third of that, or 8 mrem. The 54 detector Brookhaven whole body counter was used for the absolute measurement of total body potassium (TBK).‘-’ The accuracy and precision of this counter for measuring total body potassium is _+3.3%#in an anthropomorphic phantom. With its on-line computer facility, the counter is unique, in that it has a response which is relatively invariant with respect both to the size of the individual and to the internal location of the radionuclide. Total body water was measured with the use of the standard tritiated water radioisotopic technique.” The precision of this technique is e&X’%.
Patients All patients selected for the study had histologically verified cancer. Patients with the following types of cancer were included in the study: hematological disorders (acute and chronic myeloid leukemia. chronic lymphocytic leukemia, and lymphomas), lung. gastro-intestinal, and head-neck cancer. The patient populations studied were entirely under the professional control and responsibility of the coprincipal investigator and his staff at Long Island Jewish-Hillside Medical Center. The patient groups included both patients that were expected to lose signiticant amounts of body weight in a short period of time as well as those who were expected to show little change in weight. Among the latter were patients in the early course of their disease (Stages I and II) as well as patients in Stages III and IV. some of whom might be responsive to treatment schedules. The number of patients and their cancer sites are shown in Tables 325.
tissue
compartments
tissue
in different
parameters
can
concentrations.
of body
thus
be estimated
it is possible
composition.
compartment
are more than
concentration
ratio
The
twice
to determine
as large
tissue concentration
are not completely
accurate,
problems
which
diminish
the accuracy
and precision
degree of accuracy and precision results from the use of the prompt gamma neutron activation technique. “N(n. y)“N. employed in the present study for the measurement of TBN, and from the use of a sophisticated whole body counter for the measurement of ‘OK for TBK. With the newly improved techniques for obtaining nitrogen and potassium data, it is thus possible to determine accurately TBN and TBK, in viva. The ma\s and protein content of both the muscle and the nonmuscle lean attainable.“”
A considerably
the
as the corresponding (see Appendix
A).
values used in this analysis
the mathematical
solution
of the model
Three basic assumptions are made: ( I ) that each compartment behaves as an entity with a constant ]I%]/ [K] ratio, (2) that the lipid from adipose tissue contains no K or N. and (3) that the ratio of the concentration of N to K is different in muscle and nonmuscle tissue. The assumption that each compartwill not be seriously
alfected.
ment behaves as a separate remains
to
be
assumption weight
verified.
comes
from
postsurgery.
unchanged
entity,
muscle
The
a constant
evidence
biopsies
[N]/[K]
the muscle tissue of cancer compared
patients
from
values
for the N/K
A).
These
1.
ratios
[N]/[K]
values
werr
by the finding
Abbreviations,
in the
Definitions
Drrect
Total
body
nnrogen
TBK
Total
body
potassrum
TBW
Total
body
water
B.Wt
Body
Weight
AB.Wt
Change
rn body
(body
and
less present
equations
Derivations
Ht Derrved
Body
prtor to Illness body
werghtl
hetght
Measurements
LBM
Lean body
mass
TBF
Total
fat fB.Wt
body
BCM
Body
cell mass
TBKJTBK,
Total
body
M,
Muscle
M,
Nonmuscle
M _,”
Total
P,
Protein
(see ref.
higher
(N
(TBW
(PI/O.731
(ref.
x 8.33
(see ref. 2.
10)
mass
lean body content
trssue
mass
of muscle
mass
x 6.25)
P”
Protetn
P mtn
Total
content body
of nonmuscle
protern
(ref.
measured/predrcted,
7)
mass
1)
less LMB)
TBKhnEq)
potasstum,
mass
from
ICRP23.‘-
werght
wetght
be of a
patients,
Measurements
TBN
lost
as
subjects.”
and from
used
to
ratio in
used here were taken
by Burkinshaw’”
this
who
found
muscle biopsies of four cancer
as summarized
Appendix
were
is suggested
ratio,
supports
patients
a constant
with a value of X.9 for four control
literature
[N]/[K]
that
ratios
in these patients. “I Further,
mean value of 9.0 from Mean
with
Presently.
.4
of associated
with
of the nonmuscle
[N]/[K]
in the muscle compartment
Even if the actual
Table
compartmental analysis based on TBN and TBK data was employed. This analysis provides insights into changes in body composition, particularly with respect to body weight loss. In this particular analytic technique, the differential concentration of nitrogen [N] and potassium [K] in muscle and nonmuscle lean tissue is utilired. (see Appendix. part A). The foundation I’or the present model and the analytical approach are essenttally;those of Anderson,’ who employed total body potassium and body water as the primary data. More recently, Burkinshawl” developed a mathematical model for estimating muscle and nonmuscle mass and their respective protein contents based on total body potassium and total body nitrogen. The total body nitrogen measurement technique employed by Burkinshaw is an older method based on the 14N(n, 2n)“N reaction.“.‘* and has a number
in individuals
greater accuracy than previously reported. This gain in accuracy results from the condition that the overall error in the estimates of the compartment parameters is due chiefly to the errors of measurement of TBN and TBK. and are due only to a minor extent to the variation in the assumed [K] and [N] in the tissues.‘” An advantage of the technique used in this study over other reported methods of analysis is that errors in counting resulting from differences in irradiation and detection conditions and from differences in the size and shape of the patients are considerably reduced. This reduction in error makes sequential nitrogen measurements considerably more reliable, particularly when the weight of the patient has changed significantly, as occurs in cancer patients The essentials of the technique have previously been the simplicity with which this presented,2.‘0.‘5 and demonstrate analytic procedure can be applied. (For mathematical derivation, see Appendix B.) If both K and N are found in the muscle and nonmuscle lean
1)
the
(see which
224
COHN ET AL.
Table 2.
Measured
Parameters
of Bodv Comoosition
in Male Cancer Patients
Ml?Wl B.Wt
Ht
Age
TBK
TBN
TBW
cm
-TBN
V
Kg
Kg
(1)
TBK
82.4
178.2
54
+21.0t
+4.4
Group
AB.Wt
%
Kg
Normal* (10) A. Hematol.
75.5
1.6
174.1
* 15.0
(12) B. Lung
70.4
C. GI
~ 10.7
D. Head &
- 19.0
58
66.8
-18.1
* 15.0
173.9
60
i24.0
41.6
13.1
& 13.0
k7.9
39.1 36.3
16.0 + 10.8
1.69
3.13 A6.8 2.71
+15.9
f 14.6
* 19.0
3.12 k5.8
15.7
+ 14.8
1.47 k13.0
0.106
24.0
13.5 +8.3
1.66 k16.0
0.092
+5.1
45.2 + 16.8
1.69 +16.2
0.106 t23.0
170.0
k23.0
Neck (5)
59
t4.6
56.7
k13.1
0.130 + 18.0
172.5
? 12.7
(6)
54
+4.1
f 16.7
(6)
1.90
0.141 + 16.4
TBK TBWtxw31
41.1
15.9
+7.6
* 14.7
+ 10.9 2.54 k7.7 2.58 + 19.7
( 1 = No. of patients. *Normals: 50-59y. tCV = (SD/x,
100.
constitute the model to calculate the mass of muscle and nonmuscle lean tissue, and the protein content.*.” TBK
is contained
in skeletal
As approximately
muscle,”
the muscle compartment
calculated can be considered to reflect primarily A third compartment,
tha
that the extracellular A
listing
of
(TBW)
portion of the TBW
symbols,
the skeletal muscle.
of total body fat (TBF),
mined from the total body water
definitions
employed in this study is presented
60% of the
can be deter-
measurement,
provided
is normal (see Table 1). and
compositional
ratios
in Table I.
RESULTS
The total body nitrogen (TBN), total body potassium (TBK), and total body water (TBW) data for 29 male cancer patients are presented in Table 2. For comparison, data on 10 age-matched normal males are also included. The patients with hematological malignancies (Group A) showed no significant difference in body weight when compared to the normal group. Further, the muscle mass (M,) and its protein content (P,) for the normal subjects and for patients with hematological disorders did not differ significantly. A significant loss of weight was observed in the male patients with solid tumors (Groups B, C and D). The mean weight loss (aB.Wt) was 10.7, 19.0, and
Table 3. Derived Parameters LBM Group
Kg
Normal (10)
61.9 t 16.8’
A. Hematol.
TBF
BCM
Kg
Kg
19.9
30.2
+26.0
+ 17.2
18.1%, respectively. This weight loss was calculated from the original weight before the onset of the disease (as given by the patient). Patients with head-neck, lung, and GI cancer also showed a marked decrease in muscle mass and its protein content (greater than 50%), (Table 3). This decrease was most marked in patients with GI malignancies. The mean value of the mass of the nonmuscle lean tissue (M,) appears to be larger than that of the controls, but was not significantly different from the normal control value for any of the groups of cancer patients. The mean value for total soft tissue mass (M, + M,) in groups B, C, and D showed a decrease of from 13%25%. The same decrease was noted in the mean total protein content of soft tissue in these groups ( I 1%23%). The TBN/TBK ratio for the normal male controls was 13.5, (Table 2). A slightly lower value was observed in patients with hematological disorders (Table 2). For the other groups (B, C, and D), the ratios were higher: 15.7, 16.0, and 15.9, respectively. TBN for all the groups was lower than that of the age matched male controls (1 I %23%).
of Body Composition
TBK
Mm
TBK,
1.03 26.8
in Male Cancer Patients M”
M “,.n
Pm
21.4
34.6
56.0
+31.0
t 17.0
+ 13.9
4.1 k31.0
57.7
17.4
28.0
1.02
21.5
28.8
50.3
(12) 8. Lung (6)
+14.0 53.5
k37.0 16.5
+ 18.0 22.7
t 11.4 0.85
+31.0 10.2
k22.5 38.0
+ 15.7
t35.0 6.9
t23.0 19.7
+20.6 0.82
+67.0 7.7
+19.0 34.5
+ 15.3 42.2
k67.0
C. GI (61
t 14.8 49.8
i-51.0 11.6
t15.0 22.6
k19.0 0.80
k37.0 9.2
k22.0 39.7
+12.6 48.9
+77.0
D. Head &
+ 14.6 56.3 k7.6
k63.0
+24.0
t20.0
+65.0
i-22.0
+18.2
k67.0
Neck (5)
( ) = No. of patients. ‘CV = (SD/?)
100.
P”
P“Iin
(Kg)
(Kg)
48.2
4.0 k31.0 1.9 1.4 1.7
7.8 +18.0 6.5 t24.0 8.6 k19.0 7.8 t22.0 8.9 k22.0
11.9 * 13.5 10.5 k16.4 10.5 t 14.8 9.2 k12.6 10.6 t 18.0
BODY COMPOSITION
225
OF CANCER PATIENTS
Table 4.
Measured
Parameters
of Body Composition
in Female Cancer
Patients
Meall
wt
B Group
Normal
we
TBK
TBN
TBW
cm
Y
Kg
Kg
(1)
158.3
66
%
Kg
63.0
l
Ht
SB.Wt
+ 14.61
(60--69yl
0.076
1.20
TBK
TBK
28.5
+ 13.3
+ 12.5
t 5.0
TBN
15.9
k12.1
* 10’
TBW
2.66
*8.7
~5.8
(10) 66.3
A. Hematol.
0
160.4
+ 14.5
(8) B. Lung (3)
49.0
-24.8
D. Head
51.6
14.6
157.8
19.5
0.063
65 70
k5.2
31.1
1.27
28.8
1.19
0.066
20.2
28.6
18.3 + 24.0
1.11
27.4 i 14.7
+5.9 2.19
15.7
2 14.2
_t 16.4
2.64
+7.4
i27.8
+ 12.7
i-20.0
15 4
I1 1.7
417.5
0.065 +25.0
156.2
+36.0
1.27 + 12.8
k21.3
k6.5
49.6
&
Neck (6)
60
i4.6
+ 14.9
0.082 +12.5
162.6
t 10.7 C. GI (5)
54
k3.9
10.1 2.27 i4.7
16.8 i23
2.41
0
i5.7
( ) = No. of patlents. *Normals: 60-69y. tCV
(SD/%
100.
Similar data were observed for 22 female cancer patients and IO normal age matched subjects, as shown in Table 4. The weight loss of the female patients with solid tumors (groups B, C, and D) was even more marked (I 5%X%) than was observed for the male cancer patients. The decreases in muscle mass and its protein content were similar to those of the males (Table 5). The mean value of zero for M, for three female patients with lung cancer results from a small mean muscle mass of the order of the experimental error of the measure. Although the mean values of M, and M, + M, were higher than those of the controls, no significant difference was found in the mass and protein content of the nonmuscle tissue (M,) or in the lean body mass (LBM) compartment size (Table 5). The variation in each group was quite large, undoubtedly reflecting the differences in body size of the patients, dietary intake. and disease stage. The THN/TBK ratio in the normal female group and in female patients with hematological disorders was 15.9 and 15.4, respectively, and did not differ significantly (Table 4). The mean TBN/TBK ratios in
Table 5. Derived Parameters LBM
TBF
BCM
Kg
Kg
Kg
23.3
16.3
~27.0
_t 12.6
Group Normal
(10) A. Hematol. (81 B. Lung (3)
39.0 i 12.01 42.7 t11.7 39.6 t27.5
C. GI (5)
38.3 + 14.2
D. Head & Neck (6)
37.6 i 14.7
( ) = No. of patients. lCV = (SD/&,lOO.
24.3
17.6
z 16.5
5 12.6
9.9 j 71.0 13.2 ~21.4 12.7 +57.0
13.4 t21.3 13.9 k25.0 14.1 k20.0
the patients with solid tumors (lung. G1 tract, headneck) were considerably higher; they ranged from 20.2 to 16.X. There appears to be no significant difference in TBN in all groups of female cancer patients compared with the age matched controls. Moreover, the lean body mass (LBM) in cancer patients as calculated from TBW did not differ significantly. For cancer patients (who may experience a marked loss of TBK as a response to medication). it is more appropriate to calculate LBM from total body water (TBW). Thus. the LBM obtained from TBW was used throughout to calculate the body fat (Tables 3 and 5). Data on the third compartment. body 1‘3t, can be considered together for the males and the females. There was no difference in percent body fat between patients with hematological cancer and their control group (Tables 3 and 5). However, in groups B, C, and D. the percent body fat was almost uniformly lower than that of the normal control group. Both male and female patients with Cl cancer lost. on average, 30% 40% of their body fat, while male and female patients
of Body Composition TBK
M,
M”
TBK,
0.98
in Female Cancer Patients M “7,”
P,
P,
(Kg)
(Kg)
27.7
34.5
t48.0
+ 20.8
+ 12.7
t47.0
0.98 t6.3
8.3 t44.0
28.3 t20.0
36.6 r12.2
t43.0
0.73
0
i 11.4
6.8
? 11.7 0.78 t 28.0 0.86 ? 13.4
36.6 I15.4
4.2 t99.0 5.2 +99.0
31 8 i29.0 28.2 t35.0
____ 6.
13 1.5
36.6 36.0 33.4 z 18.9
7.6 + 13.0
6.4
* 20.0 0
+ 14.9 _t 16.3
6.3 + 20.0
8.3 + 15.1
1.0 i99.0 1.0 -99.0
7.2 d29 6.3
436.0
79 Il2.9 8.3 +15 1 8.2 * 17.5 73
+20
7
226
COHN ET AL.
with head-neck cancer lost -29% of their body fat as compared to the control group. The lowest percent body fat was found in the male patients with GI and head-neck cancer. Among the female patients, those with lung cancer had the lowest percent fat. Interestingly, the lowest mean percent fat was the 12.2% observed in male GI cancer patients. This value represents a loss of 50%, as compared with the normal controls. DISCUSSION
The cancer patients whose weight losses were the largest also exhibited the greatest changes in body composition. It would be expected that the greatest loss in body weight would occur in patients with Gl and head-neck cancer, where there is interference with dietary intake. Indeed, it is the patients in these two categories who generally manifested the greatest body weight loss. However, anorexia may be as important as the mechanical effect in interfering with caloric intake, as in the above female patients with lung cancer. Like potassium, nitrogen is largely intracellular (55%). It might, therefore, be expected that levels of both would fall with tissue wasting. From the data obtained in the present study, it is clear that there is a marked reduction of skeletal muscle tissue and its protein content in patients with the solid tumors (lung, head-neck and GI tract). This finding does not hold for patients with hematological malignancies (Group A). The body composition of the latter patients does not appear to be significantly different from that of age and sex matched normal subjects. It is clear that there are differences in the potassium and the nitrogen reduction. For patients in the solid tumor groups, the TBN/TBK ratio increases from 13.4 to the range 15.7-16.0 for males, and from 15.9 to 16.8-20.2 for females. The difference in the N/K ratio derives from the greater reduction of total body potassium. Approximately 60% of TBK is contained in skeletal muscle, whereas only 45% of TBN is present in muscle (as protein). The remaining 55% of TBN is in bone collagen and nonmuscle lean tissue. Thus, in cancer patients, the reduction of soft tissue is primarily from the skeletal muscle compartment (M,), and the reduction of TBK is proportionately greater than that of TBN. In a previous study by Thomas et al.,18 both the potassium depletion and tissue loss were studied in patients with chronic heart disease. It was determined that the loss of weight in these patients indicated that most of the potassium reduction in men was probably due to tissue loss (if it were primarily muscle loss) and that there was little or no reduction in intracellular [K] in either men or women.
In the present study, the nature of the weight loss is known. The data suggest that the loss of potassium can be explained almost completely by the loss of skeletal muscle mass, the tissue with the highest concentration of potassium. Other studies, (covering a wide range of metabolic disorders), displayed a correlation of 0.88, (p < 0.0005). between TBN and TBK in a series of patients.” In these studies, no patient had a low value of TBK relative to TBN, even though many patients had a low value of TBK for their size. These data suggest that the low value of TBK reflects a reduced protein/muscle mass resulting from the disease state. It was suggested that TBK and TBN were altered proportionately.‘9 It appears questionable whether such a proportionality would remain constant in all disease conditions. For example, a differential loss of N and K has been reported for patients with uncontrolled diabetes.*’ Danowski” concluded that the loss of TBK in patients with diabetic ketoacidosis could not be accounted for by tissue breakdown alone, and suggested that most of the loss of TBK was due to the proportionately greater loss of intracellular TBK as compared with TBN. In patients treated with insulin, there was a significant increase in TBK/LBM after 6 wk.*’ Moreover, the ratio of TBK to TBN increased in all of the patients. Thus, there appears to be a disassociation between changes in TBK, TBN and LBM in patients with certain diseases (e.g., ketoacidosis). There may also be differences in the rate of loss of TBN and TBK. It is not unlikely that the loss of N occurs more gradually than the loss of K, as the increase in the loss of body tissue becomes pronounced. Atchley” presented data to show that the rates of loss of N and K were different. Conversely, in the treatment of ketoacidosis, Nabarro23 showed that the cellular retention of K occurs well before the retention of N. Dabek et al.‘4 have reported a correlation of TBN and TBK of 0.96, with a coefficient of variation about the regression line of 4% for normal subjects. For patients with cancer and other endocrine and renal diseases, the correlation coefficient was 0.92, with a CV of 8%. These authors noted further that in wasting diseases, the N/K ratio increased from a mean of 12.6 in male control subjects to 15.7 in male patients and 16.5 in female patients. These findings are consistent with the observations in the present study. The increase observed in the patients was ascribed to the greater loss of the potassium-rich muscle, as compared with the loss of skeletal tissue with its much lower potassium concentration.24 That there is a marked deficit in TBK in the cancer patients with solid tumors can be seen in the TBK/ TBK, ratio (i.e., measured to predicted total body
BODY COMPOSITION
OF CANCER PATIENTS
potassium) (Tables 3 and 5). In the patients with solid tumors, the mean TBK deficit was 0.80 to 0.85 in male patients, and 0.73 to 0.86 in female patients. A rather wide range of values for the N/K ratio (I 0 to 18) was determined for normal men and women in a study by McNeill,” which utilized partial body neutron activation for the measurements. Males were found to have a mean N/K ratio of 12.5 i 12%, and females a mean ratio of 14.6 i 14.8%. These values correspond to those determined in the present study: 13.5 i 8.3% for the TBN/TBK ratio for normal males, and 1S.9 t 8.7% for normal females. In a group of malnourished patients, again measured by partial body neutron activation, McNeill*’ found the N/K ratio for the male and female population to be 13.0 and 13.8, respectively. These TBN/TTBK values do, however. differ from those obtained for the cancer patients in the present study. The corresponding mean N/K ratios for male and female cancer patients were 15.9 and 18. I, respectively. It is to be noted, of course, that malnourished patients and cancer patients represent two different populations. The smaller variation in the results of the present study, which employs total body neutron activation as compared to the partial body neutron activation study previously discussed, most likely reflects the smaller experimental error in the measurements of nitrogen and potassium, and also the elimination of the extrapolation that is required for the interpretation of partial body TBN data. It does appear, however, that TBK is not a good predictor for TBN in patients with wasting diseases, as was concluded by McNeill.” As McNeil1 points out, the nitrogen content in an individual by ilself is of little diagnostic value unless normalized for body size. A first approximation was obtained with the use of a regression curve for the data on nitrogen as a function of the second power of height (Ht’).“’ However, with this normalization there is a wide spread of data about the regression line (20%‘). A more effective normalization is required for individuals, similar to that developed for TBK.’ Analysis of the data leads to the question of whether the loss of TBK seen in patients with wasting diseases can be ascribed entirely to the loss of TBK associated with loss of muscle, or whether it can be partially ascribed to cell depletion of K. Data from the present study suggest that the loss of K can be accounted for primarily by the loss of skeletal muscle mass. The loss of TBN appears to be small in the male cancer patients and virtually negligible in female cancer patients. These differences, however. may reflect the lack of normalization of the TBN for body size of these patients. It is also possible that the measured nitrogen reflects the size of the tumor mass. The loss of body weight by patients with solid
227
tumors consists primarily of the loss of muscle mass and body fat. Fat is the most variable component of body composition. Again, it is difficult to generalize on the basis of the changes produced in this heterogeneous group of patients. The maximum mean percent fat lost was 50%. Thus, even in severe wasting, the patients appear to retain large amounts of body fat. This retention of sizable amounts of body fat, while unexpected, is consistent with the observations of Moore et al. in patients with wasting diseases.‘.‘h The loss of TBW appears to be only slight in the cancer patients studied. The BCM loss in these patients with wasting diseases is significant, but not as marked as the loss of muscle mass. Thus, the ratio of TBK/TBW is lower in cancer patients with Cl. headneck and lung cancer. This finding suggests that the hydration of lean body tissues in cancer patients may be higher than the value assumed for normal subjects. 0.73. BCM is, as defined by Moore,” comprised of three fractions: (I) skeletal and smooth muscle (60%), (2) life supporting body components (viscera, brain, liver. kidney, etc.), l5%, and (3) low energy metabolized extracellular tissue (skeleton, cartilage, tendons, fascia and skin), 25%. As Moore pointed out in 1963, there is every reason to believe that skeletal muscle is preferentially lost in wasting diseases.’ Its size diminishes, as noted by physical examination or by weight on dissection. or indirectly, by the K/creatinine ratio. Moore also pointed out that viscera (heart and liver) tend to become enlarged with disease.’ The data in the present study obtained by direct measurement of TBN, TBW and TBK clearly corroborate the above clinical observations and isotopic analyses. In patients with severe wasting, it is the skeletal muscle mass that is predominantly lost, and not the visceral life-supporting system. The nonmuscle tissue (M,) or visceral fraction did not change in this study. and actually appears to increase in size when compared to the normal contrast population. Clearly. the prompt gamma neutron activation and whole body counting techniques represent a considerable advance over the balance and radioisotope techniques used in earlier studies. The new techniques make possible sequential studies of TBN and TBK over prolonged periods of time with a considerable degree of accuracy. In addition, they are both noninvasive techniques, and they present a minimum of inconvenience for the patient. Validation of the compartmental analysis technique for estimation of muscle and nonmuscle must ultimately be obtained from direct analysis of human cadavers. The comparison of the present derived values for the several components of body composition correspond well with those reported from the dissection and analysis of a cadaver
COHN ET AL.
of a female cancer patient.26 The procedure is extremely difficult to carry out, and subject to significant error. As has been previously pointed out,2 there are few data available with which to compare the results of this compartmental analysis of body composition. However, the muscle mass (M,) reported in the present study closely compares with that reported by Anderson’ who used TBK and TBW (rather than TBN) for his analysis of normal subjects. Thus, the accuracy of the model has still to be firmly established. It should be clear that the loss of body weight, and hence changes in body composition due to the disease process cannot be distinguished from the losses due to decreased dietary intake or a decrease in intestinal absorption. The effects of therapy in this heterogeneous group of cancer patients cannot easily be separated. These factors are in addition to the parameters of age, sex, and body size, which also influence body
composition both in normal subjects and in patients with wasting diseases. It will be the object of further studies to separate out the many factors that cause changes in body composition in cancer patients. ACKNOWLEDGMENT The authors wish to acknowledge the contribution to the study of the following BNL personnel: S. Minton. B.S., and A. Kronenberg, B.S.. for their participation in the measurement of total body nitrogen; M. Stravino. CRT, LRT. and J. Rothmann, who performed the total body potassium and calcium measurements; A. F. LoMonte, MS., who performed the total body water measurements, and F. O’Brien, who served as coordinator for the scheduling of subjects participating in this project. The authors also wish to thank the following Long Island Jewish-Hillside Medical Center personnel, who contributed to this study: M. Brandys, who served as data manager at L.I.J.; J. Stein, R.N.. who coordinated Brookhaven visits and accompanied the patients on these visits; E. Ippolito. who collated and analzyed the patient’s diet history and performed anthropometric measurements: M. Trolio, who also served as coordinator and liaison for the Brookhaven visits of patients.
REFERENCES 1. Moore FD, Olesen KH. McMurrey JD, et al: The Body Cell Mass and Its Supporting Environment: Body Composition in Health and Disease. Philadelphia, W. B. Saunders, 1963, pp 173-223 2. Cohn SH, Vartsky D, Sawitsky A, et al: Compartmental body composition based on total body nitrogen, potassium and calcium. Am J Physiol (in press) 3. Vartsky D, Ellis KJ, Cohn SH: In viva measurement of body nitrogen by analysis of prompt-gamma from neutron capture. J Nucl Med 20:1158, 1979 4. Vartsky D, Prestwich WV, Thomas BJ, et al: The use of body hydrogen as an internal standard in the measurement of nitrogen by in vivo prompt-gamma capture gamma ray analysis. J Radioanal Chem 48:243, 1979 5. Cohn SH, Dombrowski CS, Pate HR, et al: A whole-body counter with an invariant response to radionuclide distribution and body size. Phys Med Biol 14:645, 1969 6. Cohn SH, Dombrowski CS: Absolute measurement of whole body potassium by gamma spectroscopy. J Nucl Med 1 I :239. 1970 7. Ellis KJ. Shukla KK, Cohn SH: A predictor for total-body potassium in man based on height. weight, sex and age: Application in metabolic disorders. J Lab Clin Med 83:716, 1974 8. Vaughan BE. Boling EA: Rapid assay procedures for tritium labeled water in body fluids. J Lab Clin Med 57: 159, 1961 9. Anderson EC: Three component body composition analysis based on potassium and water determination. Ann NY Acad Sci I lO:l89, 1963 IO. Burkinshaw L. Hill CL, Morgan DB: Assessment of the distribution of protein in the human by in viva neutron activation analysis. Int Symp on Nucl Activation Techniques in the Life Sciences, May 1978, IAEA, Vienna, IAEA-SM-227/39 1 I. Cohn SH, Dombrowski CS: Measurement of total-body calcium, sodium, chlorine, nitrogen and phosphorus in man by in viva neutron activation analysis. J Nucl Med 12:499, 197 I 12. Oxby CB. Appelby DB. Brooks K, et al: A technique for measuring total body nitrogen in clinical investigations using the 14N(n.2n) “N reaction. Int J Appl Rad lsot 29:205. 1978 13. Vartsky D, Thomas BJ, Prestwich WV: Comparison of the spatial uniformity of sensitivity of neutron activation techniques for whole body nitrogen measurements. Kerntechnik 18:304, 1976 14. Leach MO, Thomas BJ. Vartsky D: Total body nitrogen
measured by the 14N(n, 2n) 13N method: A study of the interfering reactions and the spatial sensitivity with depth. Int J Appl Rad lsot 28:263, 1977 IS. Cohn SH, Sawitsky A. Vartsky D, et al: In viva quantification of body composition in normal subjects and cancer patients. Int J Nutr Cancer 2:67, 1980 16. Heymsfield S: Personal communication 17. Report of Task Group on Reference Man. International Commission on Radiological Protection, No. 23. New York, Academic Press, I975 18. Thomas RD. Burkinshaw L. Silverton NP, et al: Potassium depletion and tissue loss in chronic heart disease. Lancet July 7, 9, 1979 19. Harvey TC. Dykes PW, Chen NS, et al: Measurement of whole body nitrogen by neutron activation analysis. Lancet 2:395, 1973 20. Walsh CH, Soler NC, James H, et al: Studies in whole body potassium and whole body nitrogen in newly diagnosed diabetes. Q J Med l78:295, 1976 21. Danowski TS, Peters JH, Rathburn JC. et al: Studies diabetic acidosis and coma, with particular emphasis on retention administered potassium. J Clin Invest 28: I. I949
in of
22. Atchley DW, Loeb RF, Richards DW, et al: On diabetic acidosis: Detailed study of electrolyte balances following withdrawal and reestablishment and insulin therapy. J Clin Invest 12. 297, 1933 23. Nabarro JDN, Spencer AC. Stowers JM: Metabolic in severe diabetic ketosis. Q J Med 21:225, 1952
studies
24. Dabek JT, Vartsky D, Dykes PW, et al: Prompt gamma neutron activation to measure whole body nitrogen absolutely: Its application to studies of in viva changes in body composition in health and disease. J Radioanal Chem 37:325, 1977 25. McNeil1 KG, Mernagh JR, Jeejeebhoy KD, et al: In viva measurements of body protein based on the determination of nitrogen by prompt--y analysis. Amer J Clin Nutr 32, 1955, 1979 26. Moore FD, Lister J, Boyden CM, et al: The skeleton as a feature of body composition: Values predicted by the isotope dilution and observed by cadaver dissection in an adult female. Human Biol 40: 135. 1968
BODY COMPOSITION
OF CANCER PATIENTS
229
APPENDIX A Concentration
1Klg/Kg Muscle
of K and N in Lean
D’ldKg
the value
[Nl/[Kl
30
3.55
Body Compartments
8.45
[N]
Nonmuscle
[K]
in muscle
in muscle
I .87
36
19.25
Values standard
The above were
values taken
employed from
Report
in the compartmental
Burkinshaw.”
He derived
tional
APPENDIX Derivation Ii - K,
N -
of Equations
4 K,
iv, t
Commission
in nonmuscle
[K]
are
ofTuskGroup
and [N]
presented on
mean
of
His value for
(17)as are the lean tissue.
in over 100 tissues in in
Table
Kejkwtc~c~
on Radiological
IOX of
Man
the
(Interna-
Protection).”
B
for Compartmental
(1)
N,
for both man
as a weighted
in the literature.
is based on ICRP-23
values of [K] and [N]
lean
analysis
for
eleven values presented
It follows
Model
that:
(2) (9)
A’ = total body potassium K,
= potassium
in muscle
k, = potassium N = total
r
Hence
in nonmuscle
body nitrogen
M,,=
in muscle
N, = nitrogen
in nonmuscle
_
-.
K
lean tissue
rn, ~ C_
(3);
(4);
111
Substitution
r.. = rn -2
(5)
rK y r,K,
r-k’
t
= =
,k.: In similar
r,K,,
f
r,(K
19.25 I X.45 See Appendix 3.55
r,K,
(6)
M, =-
rrrl K
N
.W
1K ,,1(r,,, -- r,, 1
~ K,)
(7)
:1/,,, ~~
r,r,K rn
Since
12
manner:
of ( I ) into (6): -7
(10)
-
n
of (3). (4). and (5) into (2) yields:
and by substitution
19.25 K - ‘2: 38.34
N, = nitrogen N
lean tissue
K, - [K,]M, [K,]= Concentration of K in muscle M,,, = mass of muscle
(8)
r,N rm
rmrnK ~ r,N N,, 7 _ r 111 rn
8.4SK
20.30 K
0.052x 0.066
O.llX;~
0.066
(II) (12)
K (13)
A. Sawitsky,
K. J. Ellis, S. Yasumura, Quantitative
nitrogen
measurement
was
measured
was made of body composition by means
determined
of the
prompt
with the use of a whole body counter.
lean tissue were simultaneously inferred.
estimated
by application
with the use of tritium
The prompt
gamma
over prolonged
wasting,
predominantly
activation
the
appear
and whole
did not change
with the normal contrast
consisted
Medical
Upton.
York
Address
reprint
Island
Deparrmeni
in part of
Medical
to
Dr.
S.
Department.
H.
National
Labo-
Energy.
Manuscript
CC‘, 1981 by Grune & Stratton, 0026-0495/81/3003-0003$01.00/0
Inc.
analysis.
techniques
Total
was
and nonmuscle
body water,
represent
determined
a considerable
advance
make possible sequential
studies
of the loss of muscle mass and body fat. Even
of body
fat.
It is the skeletal
muscle
extent, spared. The nonmuscle to increase
in size when
which
is
tissue including
comparison
was made
has
made of body composition in patients with various forms of neoplastic disease. Total body nitrogen is determined with the use of the prompt gamma neutron activation technique, while total body potassium is measured with the use of a whole body counter. The mass and protein content of the muscle compartment and the nonmuscle lean tissue are estimated by application of a technique of compartmental analysis. Total body water, determined simultaneously with the use of a tritium label, provides a measure of lean body mass. From these data. the body fat can be inferred. Baseline data on body composition of age and sex matched individuals which have already been obtained in an earlier study’ provide a basis for comparison and evaluation. The work covered in the present study is part of a larger study of the dynamic changes in total body nitrogen, potassium and water in cancer patients as a function of time and in relation to the loss of body weight. Following this study, the effect of various regimens of hyperalimentation on body composition will be investigated. The assessment of body cell mass of cancer patients, and the effect on it of various nutritional regimens, is of primary importance in developing appropriate management programs for these patients. Thus, the elucidation of the relationships under study should serve to improve the clinical programs of cancer patients. MATERIALS
Cohn,
Brookhaven
Upton, N. Y. 11970.
by DE-AC02-76CH00016
contract NIH-NCIYOI-CP-80207.
potassium
Jewish-Hillside
April 8. 1980.
requests
Laboratory,
Supported
222
Long
Center, New Hyde Park, New York 11042.
Received for publication National
11973:
disease. Total body
body
The loss of total body water was slight in the cancer patients studied.
Research Center, Brookhaven
New
primarily
amounts
system is, to a considerable
EASUREMENTS of changes in body composition which result from chronic wasting diseases are of great importance, both in evaluation of the status of the patient, and in the determination of appropriate patient management regimens. Of particular interest are the relative proportions of body cell mass, fat, and water. The significant changes that occur in body weight of cancer patients are well known. Further, studies have revealed a decrease in both total body potassium (TBK) and total body nitrogen (TBN) in these patients, associated with this loss of tissue.‘*2 However, the detailed nature of the relationship between the deficits of these two elements is not known. Until very recently, indirect measurement of body composition has been the chief source of data.’ Presently, however, some indirect measurements made by means of balance studies or radioisotopic studies, can be replaced with direct measurements by the application of the nuclear techniques of neutron activation and whole body gamma spectrometry. These latter measurements have both enlarged and refined the data base for the quantification of body compartments. In the present study, quantitative measurement is
From the Medical
body counting
significant
M
ratory,
total
of lean body mass. From these data, the body fat can be
in this study, and actually appeared
population.
technique;
degree of accuracy.
to retain
lost: the visceral life-supporting
the visceral fraction
activation
of compartmental
a measure
by patients with solid tumors
patients
neutron
used in earlier studies. The new techniques
periods of time with a considerable
The loss of body weight in severe
in patients with several forms of neoplastic
gamma
of the technique
techniques
and D. Vartsky
The mass and protein content of the muscle compartment
label, provided
neutron
over the balance and radioisotope
K. Rai, I. Zanzi, A. Vaswani,
E. Cortes,
with
the U.S.
been authored
under
AND
METHODS
Instrumentation The prompt gamma neutron activation facility measures total body nitrogen (TBN) with an accuracy and precision of *3% in the anthropomorphic phantom utilized.3 A detailed description of the prompt gamma neutron activation technique, 14N(n, y)“N, for the absolute measurement of whole body nitrogen has been presented.’ The detector geometry yields a quite uniform composite sensitiv-
Metabolism,
Vol. 30, No. 3 (March), 1981
BODY
COMPOSITION
ity (i.e., an equal
OF CANCER
number
223
PATIENTS
of counts
per unit mass of nitrogen
per
unit dose). The use of an internal standard based on body hydrogen further increases the uniform composite sensitivity and hence increases the accuracy of the measurement4 The present method of nitrogen measurement is reasonably comfortable. It requires only that the patient be scanned both in the prone and supine positions. With the use of restricted beam size and good collimation, the clinician or nurse may remain near the subject during the irradiation. The total radiation time is less than 20 min. and the dose equivalent delivered to the skin in this procedure is 26 mrem. A Quality Factor (QF) of 10 is assumed. The dose equivalent to the bone marrow is approximately one-third of that, or 8 mrem. The 54 detector Brookhaven whole body counter was used for the absolute measurement of total body potassium (TBK).‘-’ The accuracy and precision of this counter for measuring total body potassium is _+3.3%#in an anthropomorphic phantom. With its on-line computer facility, the counter is unique, in that it has a response which is relatively invariant with respect both to the size of the individual and to the internal location of the radionuclide. Total body water was measured with the use of the standard tritiated water radioisotopic technique.” The precision of this technique is e&X’%.
Patients All patients selected for the study had histologically verified cancer. Patients with the following types of cancer were included in the study: hematological disorders (acute and chronic myeloid leukemia. chronic lymphocytic leukemia, and lymphomas), lung. gastro-intestinal, and head-neck cancer. The patient populations studied were entirely under the professional control and responsibility of the coprincipal investigator and his staff at Long Island Jewish-Hillside Medical Center. The patient groups included both patients that were expected to lose signiticant amounts of body weight in a short period of time as well as those who were expected to show little change in weight. Among the latter were patients in the early course of their disease (Stages I and II) as well as patients in Stages III and IV. some of whom might be responsive to treatment schedules. The number of patients and their cancer sites are shown in Tables 325.
tissue
compartments
tissue
in different
parameters
can
concentrations.
of body
thus
be estimated
it is possible
composition.
compartment
are more than
concentration
ratio
The
twice
to determine
as large
tissue concentration
are not completely
accurate,
problems
which
diminish
the accuracy
and precision
degree of accuracy and precision results from the use of the prompt gamma neutron activation technique. “N(n. y)“N. employed in the present study for the measurement of TBN, and from the use of a sophisticated whole body counter for the measurement of ‘OK for TBK. With the newly improved techniques for obtaining nitrogen and potassium data, it is thus possible to determine accurately TBN and TBK, in viva. The ma\s and protein content of both the muscle and the nonmuscle lean attainable.“”
A considerably
the
as the corresponding (see Appendix
A).
values used in this analysis
the mathematical
solution
of the model
Three basic assumptions are made: ( I ) that each compartment behaves as an entity with a constant ]I%]/ [K] ratio, (2) that the lipid from adipose tissue contains no K or N. and (3) that the ratio of the concentration of N to K is different in muscle and nonmuscle tissue. The assumption that each compartwill not be seriously
alfected.
ment behaves as a separate remains
to
be
assumption weight
verified.
comes
from
postsurgery.
unchanged
entity,
muscle
The
a constant
evidence
biopsies
[N]/[K]
the muscle tissue of cancer compared
patients
from
values
for the N/K
A).
These
1.
ratios
[N]/[K]
values
werr
by the finding
Abbreviations,
in the
Definitions
Drrect
Total
body
nnrogen
TBK
Total
body
potassrum
TBW
Total
body
water
B.Wt
Body
Weight
AB.Wt
Change
rn body
(body
and
less present
equations
Derivations
Ht Derrved
Body
prtor to Illness body
werghtl
hetght
Measurements
LBM
Lean body
mass
TBF
Total
fat fB.Wt
body
BCM
Body
cell mass
TBKJTBK,
Total
body
M,
Muscle
M,
Nonmuscle
M _,”
Total
P,
Protein
(see ref.
higher
(N
(TBW
(PI/O.731
(ref.
x 8.33
(see ref. 2.
10)
mass
lean body content
trssue
mass
of muscle
mass
x 6.25)
P”
Protetn
P mtn
Total
content body
of nonmuscle
protern
(ref.
measured/predrcted,
7)
mass
1)
less LMB)
TBKhnEq)
potasstum,
mass
from
ICRP23.‘-
werght
wetght
be of a
patients,
Measurements
TBN
lost
as
subjects.”
and from
used
to
ratio in
used here were taken
by Burkinshaw’”
this
who
found
muscle biopsies of four cancer
as summarized
Appendix
were
is suggested
ratio,
supports
patients
a constant
with a value of X.9 for four control
literature
[N]/[K]
that
ratios
in these patients. “I Further,
mean value of 9.0 from Mean
with
Presently.
.4
of associated
with
of the nonmuscle
[N]/[K]
in the muscle compartment
Even if the actual
Table
compartmental analysis based on TBN and TBK data was employed. This analysis provides insights into changes in body composition, particularly with respect to body weight loss. In this particular analytic technique, the differential concentration of nitrogen [N] and potassium [K] in muscle and nonmuscle lean tissue is utilired. (see Appendix. part A). The foundation I’or the present model and the analytical approach are essenttally;those of Anderson,’ who employed total body potassium and body water as the primary data. More recently, Burkinshawl” developed a mathematical model for estimating muscle and nonmuscle mass and their respective protein contents based on total body potassium and total body nitrogen. The total body nitrogen measurement technique employed by Burkinshaw is an older method based on the 14N(n, 2n)“N reaction.“.‘* and has a number
in individuals
greater accuracy than previously reported. This gain in accuracy results from the condition that the overall error in the estimates of the compartment parameters is due chiefly to the errors of measurement of TBN and TBK. and are due only to a minor extent to the variation in the assumed [K] and [N] in the tissues.‘” An advantage of the technique used in this study over other reported methods of analysis is that errors in counting resulting from differences in irradiation and detection conditions and from differences in the size and shape of the patients are considerably reduced. This reduction in error makes sequential nitrogen measurements considerably more reliable, particularly when the weight of the patient has changed significantly, as occurs in cancer patients The essentials of the technique have previously been the simplicity with which this presented,2.‘0.‘5 and demonstrate analytic procedure can be applied. (For mathematical derivation, see Appendix B.) If both K and N are found in the muscle and nonmuscle lean
1)
the
(see which
224
COHN ET AL.
Table 2.
Measured
Parameters
of Bodv Comoosition
in Male Cancer Patients
Ml?Wl B.Wt
Ht
Age
TBK
TBN
TBW
cm
-TBN
V
Kg
Kg
(1)
TBK
82.4
178.2
54
+21.0t
+4.4
Group
AB.Wt
%
Kg
Normal* (10) A. Hematol.
75.5
1.6
174.1
* 15.0
(12) B. Lung
70.4
C. GI
~ 10.7
D. Head &
- 19.0
58
66.8
-18.1
* 15.0
173.9
60
i24.0
41.6
13.1
& 13.0
k7.9
39.1 36.3
16.0 + 10.8
1.69
3.13 A6.8 2.71
+15.9
f 14.6
* 19.0
3.12 k5.8
15.7
+ 14.8
1.47 k13.0
0.106
24.0
13.5 +8.3
1.66 k16.0
0.092
+5.1
45.2 + 16.8
1.69 +16.2
0.106 t23.0
170.0
k23.0
Neck (5)
59
t4.6
56.7
k13.1
0.130 + 18.0
172.5
? 12.7
(6)
54
+4.1
f 16.7
(6)
1.90
0.141 + 16.4
TBK TBWtxw31
41.1
15.9
+7.6
* 14.7
+ 10.9 2.54 k7.7 2.58 + 19.7
( 1 = No. of patients. *Normals: 50-59y. tCV = (SD/x,
100.
constitute the model to calculate the mass of muscle and nonmuscle lean tissue, and the protein content.*.” TBK
is contained
in skeletal
As approximately
muscle,”
the muscle compartment
calculated can be considered to reflect primarily A third compartment,
tha
that the extracellular A
listing
of
(TBW)
portion of the TBW
symbols,
the skeletal muscle.
of total body fat (TBF),
mined from the total body water
definitions
employed in this study is presented
60% of the
can be deter-
measurement,
provided
is normal (see Table 1). and
compositional
ratios
in Table I.
RESULTS
The total body nitrogen (TBN), total body potassium (TBK), and total body water (TBW) data for 29 male cancer patients are presented in Table 2. For comparison, data on 10 age-matched normal males are also included. The patients with hematological malignancies (Group A) showed no significant difference in body weight when compared to the normal group. Further, the muscle mass (M,) and its protein content (P,) for the normal subjects and for patients with hematological disorders did not differ significantly. A significant loss of weight was observed in the male patients with solid tumors (Groups B, C and D). The mean weight loss (aB.Wt) was 10.7, 19.0, and
Table 3. Derived Parameters LBM Group
Kg
Normal (10)
61.9 t 16.8’
A. Hematol.
TBF
BCM
Kg
Kg
19.9
30.2
+26.0
+ 17.2
18.1%, respectively. This weight loss was calculated from the original weight before the onset of the disease (as given by the patient). Patients with head-neck, lung, and GI cancer also showed a marked decrease in muscle mass and its protein content (greater than 50%), (Table 3). This decrease was most marked in patients with GI malignancies. The mean value of the mass of the nonmuscle lean tissue (M,) appears to be larger than that of the controls, but was not significantly different from the normal control value for any of the groups of cancer patients. The mean value for total soft tissue mass (M, + M,) in groups B, C, and D showed a decrease of from 13%25%. The same decrease was noted in the mean total protein content of soft tissue in these groups ( I 1%23%). The TBN/TBK ratio for the normal male controls was 13.5, (Table 2). A slightly lower value was observed in patients with hematological disorders (Table 2). For the other groups (B, C, and D), the ratios were higher: 15.7, 16.0, and 15.9, respectively. TBN for all the groups was lower than that of the age matched male controls (1 I %23%).
of Body Composition
TBK
Mm
TBK,
1.03 26.8
in Male Cancer Patients M”
M “,.n
Pm
21.4
34.6
56.0
+31.0
t 17.0
+ 13.9
4.1 k31.0
57.7
17.4
28.0
1.02
21.5
28.8
50.3
(12) 8. Lung (6)
+14.0 53.5
k37.0 16.5
+ 18.0 22.7
t 11.4 0.85
+31.0 10.2
k22.5 38.0
+ 15.7
t35.0 6.9
t23.0 19.7
+20.6 0.82
+67.0 7.7
+19.0 34.5
+ 15.3 42.2
k67.0
C. GI (61
t 14.8 49.8
i-51.0 11.6
t15.0 22.6
k19.0 0.80
k37.0 9.2
k22.0 39.7
+12.6 48.9
+77.0
D. Head &
+ 14.6 56.3 k7.6
k63.0
+24.0
t20.0
+65.0
i-22.0
+18.2
k67.0
Neck (5)
( ) = No. of patients. ‘CV = (SD/?)
100.
P”
P“Iin
(Kg)
(Kg)
48.2
4.0 k31.0 1.9 1.4 1.7
7.8 +18.0 6.5 t24.0 8.6 k19.0 7.8 t22.0 8.9 k22.0
11.9 * 13.5 10.5 k16.4 10.5 t 14.8 9.2 k12.6 10.6 t 18.0
BODY COMPOSITION
225
OF CANCER PATIENTS
Table 4.
Measured
Parameters
of Body Composition
in Female Cancer
Patients
Meall
wt
B Group
Normal
we
TBK
TBN
TBW
cm
Y
Kg
Kg
(1)
158.3
66
%
Kg
63.0
l
Ht
SB.Wt
+ 14.61
(60--69yl
0.076
1.20
TBK
TBK
28.5
+ 13.3
+ 12.5
t 5.0
TBN
15.9
k12.1
* 10’
TBW
2.66
*8.7
~5.8
(10) 66.3
A. Hematol.
0
160.4
+ 14.5
(8) B. Lung (3)
49.0
-24.8
D. Head
51.6
14.6
157.8
19.5
0.063
65 70
k5.2
31.1
1.27
28.8
1.19
0.066
20.2
28.6
18.3 + 24.0
1.11
27.4 i 14.7
+5.9 2.19
15.7
2 14.2
_t 16.4
2.64
+7.4
i27.8
+ 12.7
i-20.0
15 4
I1 1.7
417.5
0.065 +25.0
156.2
+36.0
1.27 + 12.8
k21.3
k6.5
49.6
&
Neck (6)
60
i4.6
+ 14.9
0.082 +12.5
162.6
t 10.7 C. GI (5)
54
k3.9
10.1 2.27 i4.7
16.8 i23
2.41
0
i5.7
( ) = No. of patlents. *Normals: 60-69y. tCV
(SD/%
100.
Similar data were observed for 22 female cancer patients and IO normal age matched subjects, as shown in Table 4. The weight loss of the female patients with solid tumors (groups B, C, and D) was even more marked (I 5%X%) than was observed for the male cancer patients. The decreases in muscle mass and its protein content were similar to those of the males (Table 5). The mean value of zero for M, for three female patients with lung cancer results from a small mean muscle mass of the order of the experimental error of the measure. Although the mean values of M, and M, + M, were higher than those of the controls, no significant difference was found in the mass and protein content of the nonmuscle tissue (M,) or in the lean body mass (LBM) compartment size (Table 5). The variation in each group was quite large, undoubtedly reflecting the differences in body size of the patients, dietary intake. and disease stage. The THN/TBK ratio in the normal female group and in female patients with hematological disorders was 15.9 and 15.4, respectively, and did not differ significantly (Table 4). The mean TBN/TBK ratios in
Table 5. Derived Parameters LBM
TBF
BCM
Kg
Kg
Kg
23.3
16.3
~27.0
_t 12.6
Group Normal
(10) A. Hematol. (81 B. Lung (3)
39.0 i 12.01 42.7 t11.7 39.6 t27.5
C. GI (5)
38.3 + 14.2
D. Head & Neck (6)
37.6 i 14.7
( ) = No. of patients. lCV = (SD/&,lOO.
24.3
17.6
z 16.5
5 12.6
9.9 j 71.0 13.2 ~21.4 12.7 +57.0
13.4 t21.3 13.9 k25.0 14.1 k20.0
the patients with solid tumors (lung. G1 tract, headneck) were considerably higher; they ranged from 20.2 to 16.X. There appears to be no significant difference in TBN in all groups of female cancer patients compared with the age matched controls. Moreover, the lean body mass (LBM) in cancer patients as calculated from TBW did not differ significantly. For cancer patients (who may experience a marked loss of TBK as a response to medication). it is more appropriate to calculate LBM from total body water (TBW). Thus. the LBM obtained from TBW was used throughout to calculate the body fat (Tables 3 and 5). Data on the third compartment. body 1‘3t, can be considered together for the males and the females. There was no difference in percent body fat between patients with hematological cancer and their control group (Tables 3 and 5). However, in groups B, C, and D. the percent body fat was almost uniformly lower than that of the normal control group. Both male and female patients with Cl cancer lost. on average, 30% 40% of their body fat, while male and female patients
of Body Composition TBK
M,
M”
TBK,
0.98
in Female Cancer Patients M “7,”
P,
P,
(Kg)
(Kg)
27.7
34.5
t48.0
+ 20.8
+ 12.7
t47.0
0.98 t6.3
8.3 t44.0
28.3 t20.0
36.6 r12.2
t43.0
0.73
0
i 11.4
6.8
? 11.7 0.78 t 28.0 0.86 ? 13.4
36.6 I15.4
4.2 t99.0 5.2 +99.0
31 8 i29.0 28.2 t35.0
____ 6.
13 1.5
36.6 36.0 33.4 z 18.9
7.6 + 13.0
6.4
* 20.0 0
+ 14.9 _t 16.3
6.3 + 20.0
8.3 + 15.1
1.0 i99.0 1.0 -99.0
7.2 d29 6.3
436.0
79 Il2.9 8.3 +15 1 8.2 * 17.5 73
+20
7
226
COHN ET AL.
with head-neck cancer lost -29% of their body fat as compared to the control group. The lowest percent body fat was found in the male patients with GI and head-neck cancer. Among the female patients, those with lung cancer had the lowest percent fat. Interestingly, the lowest mean percent fat was the 12.2% observed in male GI cancer patients. This value represents a loss of 50%, as compared with the normal controls. DISCUSSION
The cancer patients whose weight losses were the largest also exhibited the greatest changes in body composition. It would be expected that the greatest loss in body weight would occur in patients with Gl and head-neck cancer, where there is interference with dietary intake. Indeed, it is the patients in these two categories who generally manifested the greatest body weight loss. However, anorexia may be as important as the mechanical effect in interfering with caloric intake, as in the above female patients with lung cancer. Like potassium, nitrogen is largely intracellular (55%). It might, therefore, be expected that levels of both would fall with tissue wasting. From the data obtained in the present study, it is clear that there is a marked reduction of skeletal muscle tissue and its protein content in patients with the solid tumors (lung, head-neck and GI tract). This finding does not hold for patients with hematological malignancies (Group A). The body composition of the latter patients does not appear to be significantly different from that of age and sex matched normal subjects. It is clear that there are differences in the potassium and the nitrogen reduction. For patients in the solid tumor groups, the TBN/TBK ratio increases from 13.4 to the range 15.7-16.0 for males, and from 15.9 to 16.8-20.2 for females. The difference in the N/K ratio derives from the greater reduction of total body potassium. Approximately 60% of TBK is contained in skeletal muscle, whereas only 45% of TBN is present in muscle (as protein). The remaining 55% of TBN is in bone collagen and nonmuscle lean tissue. Thus, in cancer patients, the reduction of soft tissue is primarily from the skeletal muscle compartment (M,), and the reduction of TBK is proportionately greater than that of TBN. In a previous study by Thomas et al.,18 both the potassium depletion and tissue loss were studied in patients with chronic heart disease. It was determined that the loss of weight in these patients indicated that most of the potassium reduction in men was probably due to tissue loss (if it were primarily muscle loss) and that there was little or no reduction in intracellular [K] in either men or women.
In the present study, the nature of the weight loss is known. The data suggest that the loss of potassium can be explained almost completely by the loss of skeletal muscle mass, the tissue with the highest concentration of potassium. Other studies, (covering a wide range of metabolic disorders), displayed a correlation of 0.88, (p < 0.0005). between TBN and TBK in a series of patients.” In these studies, no patient had a low value of TBK relative to TBN, even though many patients had a low value of TBK for their size. These data suggest that the low value of TBK reflects a reduced protein/muscle mass resulting from the disease state. It was suggested that TBK and TBN were altered proportionately.‘9 It appears questionable whether such a proportionality would remain constant in all disease conditions. For example, a differential loss of N and K has been reported for patients with uncontrolled diabetes.*’ Danowski” concluded that the loss of TBK in patients with diabetic ketoacidosis could not be accounted for by tissue breakdown alone, and suggested that most of the loss of TBK was due to the proportionately greater loss of intracellular TBK as compared with TBN. In patients treated with insulin, there was a significant increase in TBK/LBM after 6 wk.*’ Moreover, the ratio of TBK to TBN increased in all of the patients. Thus, there appears to be a disassociation between changes in TBK, TBN and LBM in patients with certain diseases (e.g., ketoacidosis). There may also be differences in the rate of loss of TBN and TBK. It is not unlikely that the loss of N occurs more gradually than the loss of K, as the increase in the loss of body tissue becomes pronounced. Atchley” presented data to show that the rates of loss of N and K were different. Conversely, in the treatment of ketoacidosis, Nabarro23 showed that the cellular retention of K occurs well before the retention of N. Dabek et al.‘4 have reported a correlation of TBN and TBK of 0.96, with a coefficient of variation about the regression line of 4% for normal subjects. For patients with cancer and other endocrine and renal diseases, the correlation coefficient was 0.92, with a CV of 8%. These authors noted further that in wasting diseases, the N/K ratio increased from a mean of 12.6 in male control subjects to 15.7 in male patients and 16.5 in female patients. These findings are consistent with the observations in the present study. The increase observed in the patients was ascribed to the greater loss of the potassium-rich muscle, as compared with the loss of skeletal tissue with its much lower potassium concentration.24 That there is a marked deficit in TBK in the cancer patients with solid tumors can be seen in the TBK/ TBK, ratio (i.e., measured to predicted total body
BODY COMPOSITION
OF CANCER PATIENTS
potassium) (Tables 3 and 5). In the patients with solid tumors, the mean TBK deficit was 0.80 to 0.85 in male patients, and 0.73 to 0.86 in female patients. A rather wide range of values for the N/K ratio (I 0 to 18) was determined for normal men and women in a study by McNeill,” which utilized partial body neutron activation for the measurements. Males were found to have a mean N/K ratio of 12.5 i 12%, and females a mean ratio of 14.6 i 14.8%. These values correspond to those determined in the present study: 13.5 i 8.3% for the TBN/TBK ratio for normal males, and 1S.9 t 8.7% for normal females. In a group of malnourished patients, again measured by partial body neutron activation, McNeill*’ found the N/K ratio for the male and female population to be 13.0 and 13.8, respectively. These TBN/TTBK values do, however. differ from those obtained for the cancer patients in the present study. The corresponding mean N/K ratios for male and female cancer patients were 15.9 and 18. I, respectively. It is to be noted, of course, that malnourished patients and cancer patients represent two different populations. The smaller variation in the results of the present study, which employs total body neutron activation as compared to the partial body neutron activation study previously discussed, most likely reflects the smaller experimental error in the measurements of nitrogen and potassium, and also the elimination of the extrapolation that is required for the interpretation of partial body TBN data. It does appear, however, that TBK is not a good predictor for TBN in patients with wasting diseases, as was concluded by McNeill.” As McNeil1 points out, the nitrogen content in an individual by ilself is of little diagnostic value unless normalized for body size. A first approximation was obtained with the use of a regression curve for the data on nitrogen as a function of the second power of height (Ht’).“’ However, with this normalization there is a wide spread of data about the regression line (20%‘). A more effective normalization is required for individuals, similar to that developed for TBK.’ Analysis of the data leads to the question of whether the loss of TBK seen in patients with wasting diseases can be ascribed entirely to the loss of TBK associated with loss of muscle, or whether it can be partially ascribed to cell depletion of K. Data from the present study suggest that the loss of K can be accounted for primarily by the loss of skeletal muscle mass. The loss of TBN appears to be small in the male cancer patients and virtually negligible in female cancer patients. These differences, however. may reflect the lack of normalization of the TBN for body size of these patients. It is also possible that the measured nitrogen reflects the size of the tumor mass. The loss of body weight by patients with solid
227
tumors consists primarily of the loss of muscle mass and body fat. Fat is the most variable component of body composition. Again, it is difficult to generalize on the basis of the changes produced in this heterogeneous group of patients. The maximum mean percent fat lost was 50%. Thus, even in severe wasting, the patients appear to retain large amounts of body fat. This retention of sizable amounts of body fat, while unexpected, is consistent with the observations of Moore et al. in patients with wasting diseases.‘.‘h The loss of TBW appears to be only slight in the cancer patients studied. The BCM loss in these patients with wasting diseases is significant, but not as marked as the loss of muscle mass. Thus, the ratio of TBK/TBW is lower in cancer patients with Cl. headneck and lung cancer. This finding suggests that the hydration of lean body tissues in cancer patients may be higher than the value assumed for normal subjects. 0.73. BCM is, as defined by Moore,” comprised of three fractions: (I) skeletal and smooth muscle (60%), (2) life supporting body components (viscera, brain, liver. kidney, etc.), l5%, and (3) low energy metabolized extracellular tissue (skeleton, cartilage, tendons, fascia and skin), 25%. As Moore pointed out in 1963, there is every reason to believe that skeletal muscle is preferentially lost in wasting diseases.’ Its size diminishes, as noted by physical examination or by weight on dissection. or indirectly, by the K/creatinine ratio. Moore also pointed out that viscera (heart and liver) tend to become enlarged with disease.’ The data in the present study obtained by direct measurement of TBN, TBW and TBK clearly corroborate the above clinical observations and isotopic analyses. In patients with severe wasting, it is the skeletal muscle mass that is predominantly lost, and not the visceral life-supporting system. The nonmuscle tissue (M,) or visceral fraction did not change in this study. and actually appears to increase in size when compared to the normal contrast population. Clearly. the prompt gamma neutron activation and whole body counting techniques represent a considerable advance over the balance and radioisotope techniques used in earlier studies. The new techniques make possible sequential studies of TBN and TBK over prolonged periods of time with a considerable degree of accuracy. In addition, they are both noninvasive techniques, and they present a minimum of inconvenience for the patient. Validation of the compartmental analysis technique for estimation of muscle and nonmuscle must ultimately be obtained from direct analysis of human cadavers. The comparison of the present derived values for the several components of body composition correspond well with those reported from the dissection and analysis of a cadaver
COHN ET AL.
of a female cancer patient.26 The procedure is extremely difficult to carry out, and subject to significant error. As has been previously pointed out,2 there are few data available with which to compare the results of this compartmental analysis of body composition. However, the muscle mass (M,) reported in the present study closely compares with that reported by Anderson’ who used TBK and TBW (rather than TBN) for his analysis of normal subjects. Thus, the accuracy of the model has still to be firmly established. It should be clear that the loss of body weight, and hence changes in body composition due to the disease process cannot be distinguished from the losses due to decreased dietary intake or a decrease in intestinal absorption. The effects of therapy in this heterogeneous group of cancer patients cannot easily be separated. These factors are in addition to the parameters of age, sex, and body size, which also influence body
composition both in normal subjects and in patients with wasting diseases. It will be the object of further studies to separate out the many factors that cause changes in body composition in cancer patients. ACKNOWLEDGMENT The authors wish to acknowledge the contribution to the study of the following BNL personnel: S. Minton. B.S., and A. Kronenberg, B.S.. for their participation in the measurement of total body nitrogen; M. Stravino. CRT, LRT. and J. Rothmann, who performed the total body potassium and calcium measurements; A. F. LoMonte, MS., who performed the total body water measurements, and F. O’Brien, who served as coordinator for the scheduling of subjects participating in this project. The authors also wish to thank the following Long Island Jewish-Hillside Medical Center personnel, who contributed to this study: M. Brandys, who served as data manager at L.I.J.; J. Stein, R.N.. who coordinated Brookhaven visits and accompanied the patients on these visits; E. Ippolito. who collated and analzyed the patient’s diet history and performed anthropometric measurements: M. Trolio, who also served as coordinator and liaison for the Brookhaven visits of patients.
REFERENCES 1. Moore FD, Olesen KH. McMurrey JD, et al: The Body Cell Mass and Its Supporting Environment: Body Composition in Health and Disease. Philadelphia, W. B. Saunders, 1963, pp 173-223 2. Cohn SH, Vartsky D, Sawitsky A, et al: Compartmental body composition based on total body nitrogen, potassium and calcium. Am J Physiol (in press) 3. Vartsky D, Ellis KJ, Cohn SH: In viva measurement of body nitrogen by analysis of prompt-gamma from neutron capture. J Nucl Med 20:1158, 1979 4. Vartsky D, Prestwich WV, Thomas BJ, et al: The use of body hydrogen as an internal standard in the measurement of nitrogen by in vivo prompt-gamma capture gamma ray analysis. J Radioanal Chem 48:243, 1979 5. Cohn SH, Dombrowski CS, Pate HR, et al: A whole-body counter with an invariant response to radionuclide distribution and body size. Phys Med Biol 14:645, 1969 6. Cohn SH, Dombrowski CS: Absolute measurement of whole body potassium by gamma spectroscopy. J Nucl Med 1 I :239. 1970 7. Ellis KJ. Shukla KK, Cohn SH: A predictor for total-body potassium in man based on height. weight, sex and age: Application in metabolic disorders. J Lab Clin Med 83:716, 1974 8. Vaughan BE. Boling EA: Rapid assay procedures for tritium labeled water in body fluids. J Lab Clin Med 57: 159, 1961 9. Anderson EC: Three component body composition analysis based on potassium and water determination. Ann NY Acad Sci I lO:l89, 1963 IO. Burkinshaw L. Hill CL, Morgan DB: Assessment of the distribution of protein in the human by in viva neutron activation analysis. Int Symp on Nucl Activation Techniques in the Life Sciences, May 1978, IAEA, Vienna, IAEA-SM-227/39 1 I. Cohn SH, Dombrowski CS: Measurement of total-body calcium, sodium, chlorine, nitrogen and phosphorus in man by in viva neutron activation analysis. J Nucl Med 12:499, 197 I 12. Oxby CB. Appelby DB. Brooks K, et al: A technique for measuring total body nitrogen in clinical investigations using the 14N(n.2n) “N reaction. Int J Appl Rad lsot 29:205. 1978 13. Vartsky D, Thomas BJ, Prestwich WV: Comparison of the spatial uniformity of sensitivity of neutron activation techniques for whole body nitrogen measurements. Kerntechnik 18:304, 1976 14. Leach MO, Thomas BJ. Vartsky D: Total body nitrogen
measured by the 14N(n, 2n) 13N method: A study of the interfering reactions and the spatial sensitivity with depth. Int J Appl Rad lsot 28:263, 1977 IS. Cohn SH, Sawitsky A. Vartsky D, et al: In viva quantification of body composition in normal subjects and cancer patients. Int J Nutr Cancer 2:67, 1980 16. Heymsfield S: Personal communication 17. Report of Task Group on Reference Man. International Commission on Radiological Protection, No. 23. New York, Academic Press, I975 18. Thomas RD. Burkinshaw L. Silverton NP, et al: Potassium depletion and tissue loss in chronic heart disease. Lancet July 7, 9, 1979 19. Harvey TC. Dykes PW, Chen NS, et al: Measurement of whole body nitrogen by neutron activation analysis. Lancet 2:395, 1973 20. Walsh CH, Soler NC, James H, et al: Studies in whole body potassium and whole body nitrogen in newly diagnosed diabetes. Q J Med l78:295, 1976 21. Danowski TS, Peters JH, Rathburn JC. et al: Studies diabetic acidosis and coma, with particular emphasis on retention administered potassium. J Clin Invest 28: I. I949
in of
22. Atchley DW, Loeb RF, Richards DW, et al: On diabetic acidosis: Detailed study of electrolyte balances following withdrawal and reestablishment and insulin therapy. J Clin Invest 12. 297, 1933 23. Nabarro JDN, Spencer AC. Stowers JM: Metabolic in severe diabetic ketosis. Q J Med 21:225, 1952
studies
24. Dabek JT, Vartsky D, Dykes PW, et al: Prompt gamma neutron activation to measure whole body nitrogen absolutely: Its application to studies of in viva changes in body composition in health and disease. J Radioanal Chem 37:325, 1977 25. McNeil1 KG, Mernagh JR, Jeejeebhoy KD, et al: In viva measurements of body protein based on the determination of nitrogen by prompt--y analysis. Amer J Clin Nutr 32, 1955, 1979 26. Moore FD, Lister J, Boyden CM, et al: The skeleton as a feature of body composition: Values predicted by the isotope dilution and observed by cadaver dissection in an adult female. Human Biol 40: 135. 1968
BODY COMPOSITION
OF CANCER PATIENTS
229
APPENDIX A Concentration
1Klg/Kg Muscle
of K and N in Lean
D’ldKg
the value
[Nl/[Kl
30
3.55
Body Compartments
8.45
[N]
Nonmuscle
[K]
in muscle
in muscle
I .87
36
19.25
Values standard
The above were
values taken
employed from
Report
in the compartmental
Burkinshaw.”
He derived
tional
APPENDIX Derivation Ii - K,
N -
of Equations
4 K,
iv, t
Commission
in nonmuscle
[K]
are
ofTuskGroup
and [N]
presented on
mean
of
His value for
(17)as are the lean tissue.
in over 100 tissues in in
Table
Kejkwtc~c~
on Radiological
IOX of
Man
the
(Interna-
Protection).”
B
for Compartmental
(1)
N,
for both man
as a weighted
in the literature.
is based on ICRP-23
values of [K] and [N]
lean
analysis
for
eleven values presented
It follows
Model
that:
(2) (9)
A’ = total body potassium K,
= potassium
in muscle
k, = potassium N = total
r
Hence
in nonmuscle
body nitrogen
M,,=
in muscle
N, = nitrogen
in nonmuscle
_
-.
K
lean tissue
rn, ~ C_
(3);
(4);
111
Substitution
r.. = rn -2
(5)
rK y r,K,
r-k’
t
= =
,k.: In similar
r,K,,
f
r,(K
19.25 I X.45 See Appendix 3.55
r,K,
(6)
M, =-
rrrl K
N
.W
1K ,,1(r,,, -- r,, 1
~ K,)
(7)
:1/,,, ~~
r,r,K rn
Since
12
manner:
of ( I ) into (6): -7
(10)
-
n
of (3). (4). and (5) into (2) yields:
and by substitution
19.25 K - ‘2: 38.34
N, = nitrogen N
lean tissue
K, - [K,]M, [K,]= Concentration of K in muscle M,,, = mass of muscle
(8)
r,N rm
rmrnK ~ r,N N,, 7 _ r 111 rn
8.4SK
20.30 K
0.052x 0.066
O.llX;~
0.066
(II) (12)
K (13)