Albumin and fibrinogen syntheses increase while muscle protein
synthesis decreases in head-injured patients
Odile
Mansoor1,3,
Marc
Cayol2,
Pierre
Gachon3,
Yves
Boirie3,
Pierre
Schoeffler1,
Christiane
Obled2, and
Bernard
Beaufrère3
1 Département de
Réanimation, Centre Hospitalier Universitaire, 63003 Clermont
Ferrand; 2 Unité
d'Etude du Métabolisme Azoté, Institut National de la
Recherche Agronomique de Theix, 63122 St. Genès-Champandle;
and 3 Laboratoire de Nutrition
Humaine, Université d'Auvergne Centre de Recherche en Nutrition
Humaine, 63009 Clermont-Ferrand, France
 |
ABSTRACT |
The effect of trauma on protein metabolism was
investigated in the whole body, muscle, and liver in severely
head-injured patients presenting an acute inflammatory response by
comparison to fed control subjects receiving a similar diet.
Nonoxidative leucine disposal (an index of whole body protein
synthesis) and muscle, albumin, and fibrinogen synthesis were
determined by means of a primed, continuous infusion of
L-[1-13C]leucine.
Nonoxidative leucine disposal increased by 28% in the patients (P < 0.02). Fractional
muscle protein synthesis rate decreased by 50%
(P < 0.01) after injury. Fractional
and absolute fribrinogen synthesis rates were multiplied by two and
nine, respectively, after injury (P < 0.001). Albumin levels were lower in patients (25.2 ± 1.2 g/l,
means ± SE) than in controls (33.7 ± 1.2 g/l, P < 0.001). However,
fractional albumin synthesis rates were increased by 60% in patients
(11.4 ± 1.0%/day) compared with controls (7.3 ± 0.4%/day,
P < 0.01). Therefore,
1) head trauma induces opposite and
large changes of protein synthesis in muscle and acute-phase hepatic
proteins, probably mediated by cytokines, glucocorticoids, and other
stress hormones, and 2) in these
patients, hypoalbuminemia is not due to a depressed albumin synthesis.
inflammation; cytokines; leucine; tracers
 |
INTRODUCTION |
DURING THE CLASSIC "flow phase" after trauma,
critically ill patients exhibit an important loss of body proteins due
to an imbalance between proteolysis, which increases (19), and protein synthesis. Changes of protein synthesis were extensively studied at the
tissue level in numerous animal models of acute injury such as trauma,
sepsis, or pure inflammation (e.g., turpentine). Although dependent in
part on the type of injury, the most typical changes included a
depressed muscle protein synthesis (5, 10) and an increased synthesis
of total liver proteins (5, 11, 24, 31) and of positive acute-phase
proteins (18, 27, 31). Synthesis of negative acute-phase proteins
(e.g., albumin) decreases in some (4, 26, 27) if not all (18, 31)
studies, and its gene expression is depressed (21, 22). Finally,
modification of protein synthesis in other tissues, such as gut, is
more controversial (24, 11).
However, the clinical situations differ from animal models with respect
to their duration. Whereas intensive care patients frequently exhibit
severe inflammation and protein losses for days or weeks, animal
studies are performed 1-5 days (at the most) after injury and thus
might not be representative of what occurs in humans. Furthermore, few
data exist for patients; although some studies have examined whole body
protein synthesis (e.g., Ref. 14) and, more occasionally, muscle (13)
and fibrinogen or fibronectin synthesis (29), there is no comprehensive
study of these modifications in the same patients. In particular, data on albumin synthesis are extremely scarce (22). On the basis of animal
studies, albumin synthesis is widely believed to decrease (1).
Therefore, the aim of this study was to assess in critically ill
patients the modifications of protein synthesis, with simultaneous measurements at the whole body level and in muscle- and liver-derived proteins. For liver-derived proteins, we measured the synthesis of both
a positive (fibrinogen) and negative (albumin) acute-phase protein. We
chose to study severe head-injured patients for the following reasons:
1) they are known to experience a
severe muscle loss, 2) they
constitute a rather homogeneous group receiving a standardized
treatment, and 3) they have a
well-characterized and severe inflammatory response (20) even in the
absence of sepsis. These patients were compared with a group of matched
healthy subjects receiving identical nutritional intakes. The data on the proteolytic systems expression in the muscle of these patients have
been published previously (19).
 |
MATERIALS, SUBJECTS, AND STUDY PROTOCOL |
Materials, subjects, and protocol were previously described in detail
(19). Briefly, six patients with exclusive (no sepsis) and severe head
traumas were compared with five healthy volunteers matched
for age and body mass index. Patients were studied on day 8 after admission, while they were receiving continuous enteral nutrition
for at least 3 days (Nutrison
E+, Nutricia, The Netherlands, 39 ± 2 kcal · kg
1 · day
1
and 1.49 ± 0.09 g
protein · kg
1 · day
1,
means ± SE). A primed continuous (0.17 µmol · kg
1 · min
1)
infusion of
L-[1-13C]leucine
(Mass Trace, Somerville, MA) was given through a central catheter for
10 h. The pool of bicarbonate was primed with 5 mg of
NaH13CO3. Blood samples were taken
at regular intervals, and muscle biopsies were taken before and at the
end of the infusion. Indirect calorimetry was performed throughout the
study using a Deltatrac (Datex, Geneva, Switzerland) connected to the
respirator. Expired gas samples were taken in a Douglas bag at the
exhaust of the respirator during 5 min at the same times as the blood
samples. Breath samples were then transferred into Vacutainers
(Becton-Dickinson, Grenoble, France). In addition, blood samples were
also taken to measure plasma albumin, fibrinogen, orosomucoid,
C-reactive protein, haptoglobin, and cytokines at
days
4 and
8. Daily 24-h urinary excretion of
cortisol (day
8) and nitrogen (from
day 5 to day
7) were measured.
The isotopic study was performed in the control subjects in a similar
manner. The enteral diet (34 ± 2 kcal · kg
1 · day
1
and 1.40 ± 0.09 g
protein · kg
1 · day
1)
was given only during the 10 h of the tracer infusion. The infusion rate of
L-[1-13C]leucine
was 0.10 ± 0.01 µmol · kg
1 · min
1.
Indirect calorimetry was performed with the same device with the use of
a canopy.
Analytic methods.
Plasma 13C enrichments of leucine
and ketoisocaproate (KIC) were determined as previously described (19).
13C enrichments of
CO2 were measured by gas
chromatography-isotope ratio mass spectrometry (GC-IRMS, Microgas,
Fisons Instruments, Middlewich, UK). In two additional control
subjects, it was verified that the diet used in the controls (which was
made with potato maltodextrin) did not modify the natural
13C abundance in the breath (data
not shown). In the patients who received maltodextrins made from corn,
the basal 13C abundance was higher
but was stable throughout the study, since this diet had been
continuously administered for at least 3 days before the isotopic
study.
Incorporation of
[13C]leucine into the
muscle proteins was measured by GC-combustion-IRMS (Isochrom, Fisons
Instruments) according to Yarasheski et al. (32) with slight
modifications. Briefly, 10-15 mg of muscle were powdered in liquid
nitrogen and homogenized in trichloroacetic acid (TCA). The protein
pellet was washed with TCA, hydrolyzed, filtered, and dried.
N-acetyl propyl derivatives of leucine
were separated from other amino acids onto a nonpolar GC column, and
the leucine peak was directed through the furnace, where combustion in
CO2 occurred.
CO2 was then directed toward the
IRMS in alternation with pulses of reference
CO2 gas. Each sample was injected
five to six times, and the mean coefficient of variation (CV) of
replicates was 8% (range 4-11%). Standard curves covering a
range of similar enrichments (0-0.005 atom percent excess,
r2
0.99) were
run simultaneously.
[13C]leucine
enrichments in albumin and fibrinogen were also determined by
GC-combustion-IRMS, as previously described (9). Purity of the isolated
fractions was checked by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis in both controls and patients (data not shown). Plasma
protein (except fibrinogen) concentrations were measured by
immunonephelometry. Fibrinogen concentration was determined by a
turbidimetric assay (Biodirect, Les Ulis, France).
Calculations.
Whole body leucine flux and oxidation were calculated at steady state,
using the plasma
[13C]KIC enrichment as
the precursor pool. CO2 recovery
factors of 0.82 in the controls and 0.90 (30) in the patients were
used. Nonoxidative leucine disposal, an index of whole body protein synthesis, was the difference between flux and oxidation. Leucine balance was calculated as leucine intake, including the tracer infusion
rate minus oxidation.
Muscle fractional synthesis rate (FSR, in %/day) was calculated as the
ratio between the
[13C]leucine
incorporation in muscle (i.e., enrichment at time 10 h minus
natural abundance at time
0) and the plasma
[13C]KIC enrichment
at plateau, multiplied by 2.4. The
[13C]leucine
incorporation rate into albumin and fibrinogen was calculated between time 6 and 10 h by least square regression analysis.
FSRs were then obtained by dividing the slopes of incorporation
(corrected for 24 h) by the plasma
[13C]KIC
enrichment at plateau. Absolute synthesis rates (ASR, in mg
protein · kg
1 · day
1)
were then calculated as FSR (%/day) times plasma albumin or fibrinogen
concentrations (mg/ml) times plasma volume (ml/kg). The latter was
calculated from the estimated blood volume (69 ml/kg in men, 65 ml/kg
in women) (17) and the measured hematocrit.
Statistical analysis.
All values are expressed as means ± SE. Between groups comparisons
were made by two-tailed unpaired
t-tests. Data in Table 1 (controls and trauma patients at
day 4 and day
8) were compared by analysis of
variance, followed by a Scheffé test.
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Table 1.
Plasma protein concentrations in control subjects and in head-injured
patients at days 4 and 8 after admission
|
|
 |
RESULTS |
All the patients were in negative nitrogen balance (19). Their energy
expenditure was similar to that of the controls (31.9 ± 3.6 and
26.8 ± 1.2 kcal · kg
1 · day
1,
not significant), and their respiratory quotient was higher (0.95 ± 0.04 and 0.84 ± 0.01, P < 0.05).
As shown in Table 1, patients had a severe biological inflammatory
response increasing from day
4 to
day
8, as assessed by high plasma levels
of C-reactive protein, orosomucoid, haptoglobin, and fibrinogen. By
contrast, plasma albumin concentrations decreased in the patients, the
decrease being significant only at day
8. Plasma levels of interleukin-1
(IL-1
) and interleukin-6 (IL-6), but not of tumor necrosis
factor (TNF), were elevated, and so were cortisoluria (19). Hematocrit at day
8 was lower in the patients (31 ± 2%) than in the controls (46 ± 1%,
P < 0.001), and the calculated
plasma volume was therefore higher in the patients than in the controls
(46 ± 1 vs. 37 ± 1 ml/kg, respectively,
P < 0.001).
Plateaus of leucine and KIC enrichments were obtained in all subjects
after 2 h of infusion. Whole body leucine flux was increased by 50% in
the patients (P < 0.001), as
previously reported (19). Leucine oxidation was doubled
(P < 0.01), and nonoxidative leucine disposal increased by 28% in patients
(P < 0.02; Table
2). Leucine balance was positive during
feeding in the controls, whereas it remained negative in the patients
(P < 0.01). Similar qualitative results were obtained when leucine enrichments were used instead of KIC
enrichments (data not shown).
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Table 2.
Whole body leucine kinetics measured by isotopic dilution during a 10-h
constant infusion of L-[1-13C]leucine in
enterally fed control subjects and head-injured patients 8 days
after admission
|
|
Muscle FSR was sharply decreased in the patients compared with the
controls (1.94 ± 0.23 vs. 0.86 ± 0.21%/day,
P < 0.01). The incorporation of the
tracer into albumin and fibrinogen is displayed on Fig.
1 for both the control subjects and the
patients. The slopes of incorporation were all linear (mean
r2 = 0.98 ± 0.01, range 0.91-0.99). They were greater in the patients than in
the controls, whereas the plateaus of plasma KIC enrichments were
similar in both groups. Therefore, the FSR of fibrinogen and albumin
were higher in the patients, as shown in Fig.
2 (fibrinogen FSR: 15.1 ± 1.7 vs. 28.1 ± 2.2 %/day, P < 0.001; albumin
FSR: 7.3 ± 0.4 vs. 11.4 ± 1.0 %/day,
P < 0.01 in the controls and
patients, respectively). Fibrinogen ASR was eight times higher in the
patients (75 ± 13 mg · kg
1 · day
1)
than in the controls (9 ± 1 mg · kg
1 · day
1)
(P < 0.001). Despite the decreased
albumin concentration, albumin ASR was still elevated in the patients
(133 ± 14 vs. 91 ± 5 mg · kg
1 · day
1,
P < 0.02).

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Fig. 1.
Rates of incorporation of
L-[1-13C]leucine
into albumin (A) and fibrinogen
(B) in head trauma patients ( )
and in control subjects ( ).
[13C]leucine
enrichments into proteins were measured by isotope ratio mass
spectrometry during a 10-h constant intravenous infusion of
L-[1-13C]leucine.
C: plateau of
13C enrichment into plasma
ketoisocaproate (KIC), representative of intracellular free leucine
enrichment. All data are means ± SE. APE, atom percent excess.
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Fig. 2.
Plasma concentrations, fractional synthesis rates (FSRs), and absolute
synthesis rates (ASRs) of albumin
(A) and fibrinogen
(B) in head trauma patients (filled
bars) and in control subjects (open bars). FSRs were determined by
incorporation of
[13C]leucine into
proteins during a constant 10-h infusion of
L-[1-13C]leucine,
using plasma KIC enrichment as precursor pool. ASRs were calculated as
FSR × plasma concentration × plasma volume. All data are
means ± SE; * P < 0.02, P < 0.01, P < 0.001.
|
|
 |
DISCUSSION |
The patients in this study were head trauma patients, and they might
not be representative of all the trauma situations, due to the unique
locus of injury, but, as far as acute inflammation is concerned, their
inflammatory profiles are very similar to those observed in other
traumas or sepsis. It is possible that factors other than the head
trauma itself contributed to the observed changes. For example,
prolonged immobilization reduces muscle protein synthesis (16). Also,
central catheters can induce inflammation in rats (11). However, for
ethical reasons it was not possible to fit the control subjects with
such a catheter, and, furthermore, a full surgical procedure is needed
in rats, whereas catheters are implanted percutaneously in a few
minutes in humans.
Whole body protein metabolism was assessed with the well-established
[13C]leucine method,
and our data confirm a recent study showing an increased whole body
synthesis 48 h after head injury (14). For leucine oxidation
calculations, we used a recovery factor of 0.9, which was measured in
patients, including those with head trauma, with an artificial
ventilation very similar to that of the patients in our study (30). In
any case, using any factor between 0.82 and 1.0 does not affect our
conclusions, given the large difference of leucine oxidation between
the patients and controls.
Whole body protein synthesis reflects the sum of protein synthesis
rates of all tissues and, in particular, of muscle and liver, which
together account for the major part of the whole body protein synthesis
rate. In muscle, plasma KIC enrichments slightly overestimate both
leucyl tRNA and intracellular free leucine enrichments (7), and our FSR
is thus likely to be slightly underestimated. Although this problem
could have been overcome by using the flooding dose method,
thisapproach does not allow simultaneous measurements of whole body
protein synthesis and could possibly modify protein synthesis in itself
(25). Also, the large difference of muscle FSR between the controls and
the patients was possibly overestimated because of the higher muscle proteolysis in the patients (19), probably leading to a higher dilution
of the label in the precursor pool. However, the leucyl tRNA enrichment
would have to be as low as 36% of the KIC enrichment to fully
compensate for this difference, which is highly unlikely. Furthermore,
our observation is consistent with animal and human studies performed,
with the flooding dose method showing that sepsis or inflammation in
rats (5, 10) or surgery in humans (13) all decrease muscle FSR.
Cytokines and glucocorticoids were probably responsible for this
decrease. IL-1
depresses muscle protein synthesis (5), TNF inhibits
amino acid uptake [this effect being mediated in part by
glucocorticoids (33)], and finally, IL-1 receptor antagonist
prevents the sepsis-induced inhibition of synthesis (10). Our patients
did exhibit hypercortisoluria and high plasma levels of IL-1
, but we
failed to show increased TNF levels, which are very transient and which
probably would have occurred early after admission.
The dramatic increase of fibrinogen FSR and ASR was expected,
fibrinogen being taken as a paradigm for the positive acute-phase proteins, and Thompson et al. (29) reported similar increases in three
traumatized patients. This is also consistent with the increased
expression of the fibrinogen gene in rat liver after surgery (21). IL-6
is considered as the cytokine predominantly involved in the increased
fibrinogen synthesis (8). Although the rate of synthesis of other
positive acute-phase proteins was not measured, the dramatic increase
of their concentrations suggests that their synthesis was stimulated as
well.
The issue of albumin synthesis is more complicated, since we observed
increased FSR (×1.6) and ASR (×1.5) despite
hypoalbuminemia. Albumin concentration always decreases in severe
inflammatory, septic, or injured patients and animals; for example, it
was shown to reach a nadir 7 days after injury in a large series of
head-injured patients (20). Hypoalbuminemia might be due to a reduced
synthesis or an increased degradation or an alteration of the
transcapillary escape rate. The former hypothesis is the most widely
accepted (1) on the basis of numerous animal studies showing a
decreased albumin gene expression, occurring rapidly after various
aggressions (e.g., Refs. 21 and 22). However, actual measurements of
albumin synthesis are less consistent, showing either a decrease (4, 22, 26, 27) or an increase (18, 31). A reduced dietary intake also
participates in the depressed albumin synthesis (2). Data in humans are
extremely scarce. Moshage et al. (22) reported, in four normally fed
patients with various diseases and profound hypoalbuminemia, a 25%
decrease of albumin ASR but an unchanged FSR.
Thus there is little doubt that an acute inflammation initially
depresses albumin gene expression and synthesis, which might well have
occurred in our patients and been responsible for the initiation of
hypoalbuminemia. However, the hypoalbuminemia observed later on is
actually associated with an increased albumin synthesis. This suggests
a biphasic pattern (decrease, then increase) for albumin synthesis.
Such a response was demonstrated in a prolonged animal model of sepsis
in which albumin synthesis was measured 16 (26) and 96 h (31) after
injury. Glucocorticoids are known to increase albumin synthesis in vivo
(12) and to upregulate albumin gene expression in vitro (3). In our
patients, cytokine levels (IL-6, IL-1
) were stable between
days
4 and
8, whereas cortisoluria doubled over
the same period (19). Therefore, we could speculate that
glucocorticoids mediate the secondary increase of albumin synthesis.
Alternatively, plasma amino acids and particularly leucine
concentrations were possibly elevated in the patients due to their
higher proteolysis (and to the slightly higher rate of tracer
infusion). They could stimulate albumin synthesis, as demonstrated in
cancer patients fed with a branched-chain amino acid formula (28). The
persistent hypoalbuminemia could be explained by an escape of plasma
albumin in the extravascular space. In this respect, the albumin
transcapillary escape rate was found to be increased by
50-300% in critically ill (15) and in infected patients (6).
Also, IL-1
was reported to dramatically increase albumin transfer
across endothelial cells (20). However, the positive correlation
between albumin levels and its transcapillary escape rate reported by
Ballmer et al. (6) suggests that other mechanisms, such as an increased
degradation rate, could also contribute to hypoalbuminemia in the
acute-phase response.
In conclusion, we demonstrated that, in continuously fed humans with
severe inflammation, there are opposite changes in the synthesis of
muscle and acute-phase hepatic protein, including albumin. This could
be interpreted as a necessity for the liver to be supplied with large
amounts of amino acids for sustaining the acute-phase hepatic response,
the amino acids being derived from increased breakdown and decreased
synthesis in muscle. This is different from what is observed in rats
with moderate inflammation, in which liver synthesis increases while
muscle is unaffected (24). Also, it was recently shown that the
reversal of muscle loss by cytokine antagonists does not affect hepatic
synthesis in septic rats (11). Therefore, further studies are needed
both in humans and animal models to establish whether or not there is a
causal relationship between changes in muscle and liver protein synthesis during severe inflammation.
 |
ACKNOWLEDGEMENTS |
We thank the staff of the Intensive Care Unit, J. Prugnaud, L. Morin, M. Genest, P. Rousset, E. Verdier, G. Manlhiot, and J. Moinard
for expert technical assistance, G. Beaujon for the cytokine assays,
and S. Samuels for helpful comments. We also thank Nutricia France for
providing the enteral products. This study was funded by grants from
Institut National de la Recherche Agronomique, Université
d'Auvergne and Région Auvergne.
 |
FOOTNOTES |
Address for reprint requests: B. Beaufrère, Laboratoire de
Nutrition Humaine, BP 321, 63009 Clermont-Ferrand Cedex 1, France.
Received 10 April 1997; accepted in final form 8 July 1997.
 |
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