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Clinical Studies |
Department of Human Biology, University of Maastricht (W.D.v.M.L.), and the Department of Internal Medicine, University Hospital Maastricht (R.-J.M.B.), Maastricht; and the Department of Endocrinology, University Hospital Utrecht (Y.E.M.S., H.P.F.K.), Utrecht, The Netherlands
Address all correspondence and requests for reprints to: Dr. Wouter D. van Marken Lichtenbelt, Department of Human Biology, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
| Abstract |
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The results show that the percent body fat was significantly (P < 0.05) higher, and total body water and intracellular water (ICW) were significantly lower in GHD adults for males, females, and both sexes combined. ECW was not significantly different between the two groups. ECW/ICW in GHD adults (0.42 ± 0.03) was significantly (P < 0.01) higher than that in controls (0.39 ± 0.02). There was a significant positive relation between the ECW/ICW ratio and the percent body fat. These results were confirmed by the bioimpedance spectrometry measurements.
| Introduction |
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The effect of GH administration on water compartments is also not unequivocal. GH treatment was shown to increase ECW in GHD adults (10, 12). However, as it is known that FFM increases with increased GH levels, it is essential to know whether the increase in ECW was relative to that in intracellular water (ICW). In another study in which ECW and ICW were determined independently, strong indications were found that GH treatment in elderly subjects results in an increase in ICW that was associated with a concomitant trend toward decreased ECW (13).
To elucidate the controversies concerning the water compartments in GHD adults, we performed a comparative study between GHD adults and controls, matched for age, sex, body weight, and height, in which TBW and ECW were determined independently using deuterium and bromide dilution as well as bioimpedance spectrometry (BIS) for predicting ECW and ICW.
| Subjects and Methods |
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Ten adult GHD patients, five men and five women, aged 2863 yr,
were included in the study. They were known to have GH deficiency for
at least 12 months (mean, 9.3 yr; range, 230 yr). In nine patients,
pituitary insufficiency was due to surgery and/or irradiation because
of a pituitary tumor. In one patient (no. 1, Table 1
),
pituitary insufficiency was caused by irradiation for nasopharynx
carcinoma.
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The plasma GH concentration was determined using a RIA from Oris Industry Co. (Gif-sur-Yvette, France), which had a lower detection limit of 0.50 ± 0.04 mIU/L (0.25 µg/L); the intra- and interassay coefficients of variation were 7.7% and 11%, respectively. Insulin-like growth factor I was measured by RIA, using the antiserum from Underword and Van Kijk, distributed by the Hormone Distribution Program of the NIDDK. All samples were run in the same assay.
The control group consisted of 10 healthy adult volunteers, matched for age, sex, body weight, and height. They were recruited before any of the measurements in the controls were carried out. The subjects were studied as out-patients at the Department of Endocrinology. All measurements were performed after an overnight fast.
The aims and methods of the study were explained to all subjects, and informed consent was obtained. The study was approved by the ethics committee of the University Hospital of Utrecht.
TBW
TBW was determined by deuterium dilution, following the method
described by Westerterp et al. (14). Subjects received an
orally administered dose of deuterium (D2O) of
approximately 0.1 g/L estimated TBW. The appropriate amount of
D2O (99.8%; Akademie der Wissenschaften, Leipzig, Germany)
was weighed out and diluted with tap water to 0.075 L for intake.
D2O enrichment in the body fluid was measured in urine.
Before treatment, background urine samples were taken. The dose was
given at 2200 h. Urine samples were taken after 10 h of
treatment from the second voiding (first voiding at
0700 h). Isotope
abundance in urine was determined in duplicate with an isotope-ratio
mass spectrometer (Aqua Sira, VG Isogas, Cheshire, UK). TBW was
calculated as the D2O dilution space divided by 1.04,
correcting for exchange of the D2O label with nonaqueous
hydrogen of body solids.
The percent BF (%BF) was calculated as follows:
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ECW
The ECW compartment was determined by bromide dilution. A known amount of sodium bromide (60 mg bromide/L estimated TBW; Ph.Eur., Genfarma, Maarssen, The Netherlands) was mixed with the D2O solution and thus administered simultaneously with the D2O dose. Venous blood samples were obtained before intake and 10 h after ingestion of bromide (16). The bromide concentration in serum ultrafiltrate was determined with high performance liquid chromatography (17). Corrected bromide space was calculated according to the method of Miller et al. (17).
BIS
BIS measures the impedance of the body at different frequencies. It is possible to discriminate between the ECW compartment and the ICW compartment of the body, as tissue impedance at low frequencies is controlled by the electrical properties of ECW and at high frequencies by the TBW compartment (ECW plus ICW). A detailed description of the method was previously reported (18, 19). Complex BIS spectra were obtained at 50 logarithmically spaced frequencies from 5500 kHz with a BIS analyzer (model 4000B, Xitron Technologies, San Diego, CA). We used a tetrapolar arrangement of gel electrodes placed on hand, wrist, ankle, and foot at the right side of the body (19). The measurements were carried out between 510 min after the subject lay supine on a bed. The impedance data were fitted to the Cole-Cole cell suspension model using nonlinear curve fitting, which revealed the ECW resistance and the intra-cellular water resistance (18, 19).
ECW and ICW volumes were predicted from a general mixture theory (18, 20). This implies that we used a formula that directly calculates the
water compartments from resistance values, assuming specific
resistances of ECW and ICW, rather than applying the common procedure
in bioimpedance analyses of an empirically determined regression
equation. The specific resistances (males:
e = 152.8,
i = 979.1; females:
e = 146.4,
i = 947) were obtained from an independent dataset at
our laboratory.
Statistics
Wilcoxons signed rank test was used to establish significance of any differences between GHD adults and matched controls. Spearman rank correlation coefficients were used to test relations between water compartments by different methods. The bias and limits of agreement between the different methods were calculated according to the method described by Bland and Altman (21). All data are expressed as the mean ± SD.
| Results |
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The absolute amounts of TBW and ICW were significantly lower in
GHD adults compared to controls (by Wilcoxon signed rank,
P < 0.05 and P < 0.02, respectively;
Table 3
), whereas ECW was not significantly different
(P > 0.1). There were no gender differences in ECW/ICW
in each group. ECW/ICW in GHD adults (0.42 ± 0.03) was
significantly (P < 0.01) higher than in that in
controls (0.39 ± 0.02). There was a significant positive relation
between the ECW/ICW ratio and the %BF (ECW/ICW = 0.63%BF + 0.49;
r2 = 0.49; P < 0.001; Fig. 1
).
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In accordance with the dilution-based results, the volume
estimations by BIS (Table 3
) revealed that TBW and ICW were
significantly lower in GHD adults than those in controls
(P < 0.05 in both cases). There were no significant
differences in ECW (P > 0.1) between GHD adults and
controls. As with the dilution techniques, the BIS results showed that
the ECW/ICW ratio was significantly higher in GHD adults than in the
control group (P < 0.01).
Comparison of dilution techniques and BIS
The regression between TBW by D2O dilution and TBW by
BIS is highly significant (r2 = 0.94; P <
0.001), with a standard error of estimate (SEE) of 1.6 L (Table 4
). Also, ECW-dilution and ECW-BIS were significantly
correlated (r2 = 0.91; P < 0.001), with a
SEE of 0.8 L. Bland Altman plots (21) reveal no significant relation
between the amount of TBW and the difference between the two methods
(Table 4
). On the average, D2O dilution revealed 1.5
± 1.6 L higher TBW values than BIS. There was a weak positive relation
between the differences in ECW by the two methods and the amount of ECW
(P < 0.05; r2 = 0.26). The mean difference
was 0.3 L.
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| Discussion |
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This study reveals that GHD adults compared to their matched controls have an enlarged ECW compartment relative to the ICW compartment, as shown by two independent methods. The difference is evident among all pairs studied. Although the GHD adults had a significantly higher %BF than the controls, the total amount of ECW was not different between GHD adults and controls, whereas ICW was significantly lower in GHD. This indicates that the increased ECW/ICW ratio in GHD adults is due to a relative decrease in ICW, rather than an increase in ECW. As suggested by Snel et al. (11), it is conceivable that in chronic GHD, the amount of ECW is in the normal range due to sodium- and water-regulating mechanisms other than GH, such as the renin-aldosterone system and/or atrial natriuretic peptide.
It is often reported that chronic GHD results in an enlarged %BF, as assessed by various methods (2, 3, 4, 12). In our study, %BF indeed is significantly increased comparied with that in the control subjects. We also found a significant positive relation between the ECW/ICW ratio and the %BF. It is well established that obese subjects have a relatively large ECW/ICW ratio (0.63 in nonobese vs. 0.81 in obese) (22, 23). This can in part be attributed to the water component of adipose tissue, which consists of 78% ECW (24). Thus, in GHD adults two compensating processes may occur: low GH concentrations result in a low ICW, and a relative expansion of body fat results in a relative expansion of the ECW. Furthermore, Waki et al. (23) suggest obesity-related edema and hormonal responses related to adipose tissue.
Finally, the decreased FFM, as shown in GHD adults, may be the result of cell shrinking (25), which, in turn, results in a decrease in ICW. This brings us to the results reported by Thompson et al. (13), who showed that GH treatment in elderly women increased the IWC compartment more than can be accounted for by the increase in FFM. This could be attributed to swelling of muscle cells.
Thus, a decreased FFM in combination with a relatively stable ECW could result in the observed increased ECW/ICW ratio.
Comparison between dilution techniques and BIS
BIS measures the impedance of the body at a whole range of frequencies instead of the classical bioimpedance analysis that uses a single frequency (mostly 50 kHz). BIS is a relatively new method that takes into account the fact that electrical resistance is frequency dependent on the electrical properties of the cell membrane. Consequently, with BIS it is possible to discriminate between ECW and ICW. At the same time, direct body fluid calculations are relatively new (18). This method has the advantage that it is not depending on empirically derived prediction formulas. However, the coefficients used for the specific resistances for ECW and ICW reflect, on the one hand, the actual specific resistances of the water compartments and, on the other hand, are dependent on the methods used to determine ECW and TBW (or ICW). In this study, bromide and D2O dilution was applied with an equilibration time of 10 h. Therefore, resistance coefficients were determined at our laboratory beforehand and independently in another group of subjects. It is important to realize that these coefficients do not affect the correlation coefficients and SEEs derived from comparisons between the water compartments by BIS and the dilution techniques.
The outcome of the comparison between the methods is promising. Despite
the low number of subjects studied, correlations of the BIS results
with the dilution techniques revealed high squared correlation
coefficients (r2
0.91) and low SEEs (TBW, 1.6 L; ECW,
0.8 L), indicating good accuracy on an individual level. The bias
between the methods was small. Clearly, a larger dataset is needed to
investigate whether the same resistance indexes can be used in
different patient groups. Very interesting for a clinical setting is
the good fit between the differences in ECW/ICW ratios between GHD
adults and controls. This indicates that changes in water compartments
and distribution of water compartments can reliably be detected by BIS.
Longitudinal intervention studies are especially necessary to further
elucidate the clinical applicability of this noninvasive fast
technique.
Received August 8, 1996.
Revised November 20, 1996.
Accepted November 28, 1996.
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