1 Department of Clinical and Experimental Medicine, Chair of Metabolism, and 2 Department of Internal Medicine, University of Padova, 35128 Padua; and 3 Department of Internal Medicine and Endocrinology, University of Bari, 70124 Bari, Italy
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ABSTRACT |
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To
investigate the anabolic effects of feeding in cirrhosis, we measured
albumin fractional synthesis rate (FSR) and whole body protein
synthesis in six nondiabetic patients with stable liver cirrhosis
(three in the Child-Pugh classification Class A, three in Class B) and
in seven normal control subjects, before and after administration of a
4-h mixed meal. Leucine tracer precursor-product relationships and
whole body kinetics were employed at steady state. Basal levels of
postabsorptive albumin concentration and FSR, whole body leucine rate
of appearance, oxidation, and nonoxidative leucine disposal (NOLD,
protein synthesis) were similar in the two groups. However, after
the meal, in the patients neither albumin FSR (from 8.5 ± 1.5 to
8.8 ± 1.8 %/day) nor NOLD (from 1.69 ± 0.22 to 1.55 ± 0.26 µmol · kg
1 · min
1)
changed (P = nonsignificant vs. basal), whereas they
increased in control subjects (albumin FSR: from 10.9 ± 1.5 to
15.9 ± 1.9 %/day, P < 0.002; NOLD: from
1.80 ± 0.14 to 2.10 ± 0.19 µmol · kg
1 · min
1,
P = 0.032). Thus mixed meal ingestion did not stimulate
either albumin FSR or whole body protein synthesis in compensated liver cirrhosis. The mechanism(s) maintaining normoalbuminemia at this disease stage need to be further investigated.
albumin synthesis; nonoxidative leucine disposal; meal
ingestion; -ketoisocaproate; specific activity; compensated
cirrhosis
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INTRODUCTION |
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LIVER CIRRHOSIS is a protein-catabolic disease, which at advanced stages is usually associated with loss of lean body mass (represented mainly by proteins and water), decreased albumin concentration, and an increased ratio of aromatic (AAA) to branched-chain amino acid (BCAA) concentrations (18, 23, 24, 39). These metabolic alterations reflect the impaired liver functional capacity and can heavily complicate the clinical course of the disease (21).
The maintenance of protein homeostasis is achieved physiologically through meal ingestion and assimilation, which counteract the interprandial catabolic phases (8, 20, 37). One key component of the anabolic response to a meal is the stimulation of protein synthesis. Indeed, in healthy humans, intake of a mixed meal of adequate amino acid and caloric content results in the acute increase of whole body, albumin, and muscle protein synthesis (8, 20, 37). However, whether these effects are preserved in cirrhosis has not been thoroughly investigated. In a previous study (3), albumin synthesis was found to be grossly unaltered in postabsorptive cirrhotic patients, but it correlated inversely with the patients' clinical status. However, the response to a mixed meal was not tested. In another study (22), no stimulation by an enteral diet of whole body protein synthesis was found in cirrhosis, although the caloric and amino acid content might have been insufficient to elicit a response (37). As a matter of fact, no study has yet investigated whether a balanced mixed meal of adequate caloric intake is capable of stimulating both whole body and albumin protein synthesis in liver cirrhosis.
The changes in body protein content as well as in plasma protein and amino acid concentrations that occur in advanced cirrhosis likely represent the end point of long-lasting alterations. Thus it is of interest to investigate whether the mechanism(s) controlling protein synthesis postprandially in cirrhosis are already altered at an early disease stage. To this aim, we have measured the response of both whole body protein and plasma albumin synthesis to mixed meal ingestion in nondiabetic, stable cirrhotic patients and in normal subjects by use of leucine tracer precursor-product relationships and whole body kinetics.
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METHODS |
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Subjects.
Six male patients with established liver cirrhosis (CP) and
seven male normal control subjects (N) were recruited. All subjects were informed about the aims of the study and signed their consent to
it. The study was approved by the Ethics Committee of the Medical Faculty at the University of Padova, Italy, and it was performed according to the Helsinki Declaration (as revised in 1983) and following the recommendations of the local Radiation Safety Officer. Whole body radiation exposure from the [14C]leucine
isotope was estimated to be 1 mGy (7). All cirrhotic subjects were ambulatory and in good health except for their liver disease. All subjects were adapted to a standard weight-maintaining diet (25-30 kcal/body wt) containing 50% of calories as
carbohydrates,
20% as proteins, and
30% as lipids for
1 yr
before the study. The diagnosis of cirrhosis was established through
medical history, clinical examination, ultrasound criteria, biochemical
data, and laparoscopy in all patients. In addition, in five patients a
liver biopsy was performed, and a chronic hepatitis C virus (HCV)
infection was diagnosed. In the sixth, nonbiopsied patient, cirrhosis
was defined as cryptogenic. Only one patient had (minimal)
endoscopic signs of esophageal varices (F1W, i.e., white
and straight varices) (4). According to Child-Pugh
classification (5, 30), three patients were in Class A and
three in Class B (Table 1). Albumin concentrations were nearly normal in most of the patients (Table 1);
therefore, their inclusion in either Child-Pugh class was due to the
other biochemical and clinical abnormalities considered by this
classification (30). In all patients, ascites was excluded through both clinical and ultrasonographic criteria. No patient had any
sign of hepatic encephalopathy or was taking any pharmacological therapy at the time of study. The patients were slightly but
insignificantly older than the controls (Table 1). However, age was
found not to affect albumin fractional synthesis rate (FSR) in humans
(11). Lean body mass (LBM, in kg) was estimated in all
subjects by Hume's formula (14). In addition, in four
cirrhotic patients, LBM was directly measured also by means of
dual-energy X-ray absorptiometry (DEXA) (17, 29). In these
patients, DEXA-determined LBM [56 ± 2 (SE) kg] was not
different from that calculated by Hume's formula (58 ± 2 kg).
Therefore, we used for all subjects the LBM values determined by
Hume's formula. In the patients, body mass index (BMI, expressed as
weight in kg divided by squared height in meters) and LBM were slightly
greater (+13 and +9%, respectively, P < 0.05) than
those measures in control subjects (Table 1), whereas the fraction of
body weight accounted for by LBM was lower (
7%, P < 0.05) (Table 1).
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Isotopes.
L-[1-14C]leucine [specific activity (SA)
2 GBq mCi/mmol] ([14C]Leu) and sodium
[14C]bicarbonate [SA
2 GBq mCi/mmol] were purchased
from Amersham (Amersham, Buckinghamshire, UK). The isotopes were proven
to be sterile and pyrogen free before use.
Experimental design.
All subjects were admitted to the Clinical Study Unit at 7:00 AM after
an overnight fast. A polyethylene catheter was placed percutaneously in
retrograde fashion into a superficial vein of one arm, which was kept
at 60°C in a heated box for arterialized venous blood sampling.
Another catheter was placed into an antecubital vein of the opposite
arm for isotope infusions. At 240 min, a primed continuous infusion
of [14C]Leu was started by means of a calibrated pump.
The rate of isotope constant infusion was 5,200-5,500
dpm · kg
1 · min
1, and the
priming dose was 60 times the constant infusion rate per minute. The
bicarbonate pool was primed with 3 µCi of
[14C]bicarbonate. Samples were frequently taken over
3 h (data not shown) to allow the achievement of steady state in
plasma leucine and
-ketoisocaproate (KIC) isotope and substrate
concentrations. Steady state was defined as absence of a slope
significantly different from 0, as well as of changes in
concentrations, specific activities, and enrichments <5%, and it was
usually achieved after
2.5 h (Fig. 1).
Between
80 and 0 min, five baseline 10-ml blood samples were
collected at 20-min intervals into EDTA tubes and rapidly centrifuged
at +4°C. The plasma was then stored at
20°C before assay. Samples
of expired air for 14CO2 measurements were
collected at the same time points.
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Analytic measurements. Plasma leucine and KIC concentrations and SA were determined by HPLC (13, 33). Plasma total amino acid concentrations were determined by ion exchange chromatography with a Beckman amino acid analyzer. The 14CO2 in the expired air was determined as described previously (33, 37). Insulin and glucagon concentrations were measured by radioimmunoassay (37). Plasma glucose was determined using a Beckman Glucose Analyzer 2.
Albumin was isolated from plasma as described previously (13), with an additional acid precipitation to avoid contamination from free amino acids. Hydrolysis was accomplished by adding 4 ml of 4 N HCl to the isolated protein and by incubating the samples in air-tight vials at 110°C for 72 h. The albumin-derived free amino acids were then further purified through cation-exchange Ag 50 × 8 columns. Leucine SA in the hydrolysate was determined by HPLC (13).Calculations. The steady-state values of plasma leucine and KIC SA in the last 80 min of the basal, postabsorptive state and in the last 80 min of meal administration (i.e., between 170 and 250 min) were averaged. All calculations were performed using these mean values.
Whole body leucine rate of appearance (Ra) was calculated using plasma [14C]KIC SA as precursor pool (32). Leucine oxidation was calculated by dividing the rate of 14CO2 expiration (in dpm · kg
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(1) |
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Statistical analysis. All data are expressed as means ± SE. The changes vs. basal within each group were analyzed with the two-tailed Student t-test for paired data. Comparison of single sets of data between the two groups (such as the relative differences vs. baseline, expressed as either percentages or deltas) was analyzed using the two-tailed Student t-test for unpaired data. The two-way ANOVA for repeated measures was also employed to compare the meal effects in the two groups simultaneously. A P value <0.05 was considered to be statistically significant.
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RESULTS |
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Albumin FSR and leucine kinetics.
In the fasting state, albumin FSR in the cirrhotic patients (CP;
8.5 ± 1.5 %/day) was slightly but insignificantly lower than that of the normal subjects [N; 10.9 ± 1.5 %/day,
P = nonsignificant (NS)]. After the meal, albumin FSR
did not change in the CP (to 8.8 ± 1.7 %/day, P = NS vs. baseline), whereas it increased in the N by an average of
45% (to 15.9 ± 1.9 %/day, P < 0.002 vs. baseline; P < 0.025 by ANOVA between groups). The
albumin FSR value in the CP during meal absorption was significantly
lower (P = 0.022) than in the N (Fig.
2).
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Plasma and albumin-bound SAs.
Albumin concentration was similar in CP and N groups (Table 1).
Postabsorptive plasma [14C]KIC SA was 2.38 ± 0.16 and 2.45 ± 0.19 dpm/nmol in CP and in N, respectively (Fig. 1).
Leucine [14C]SA was 3.09 ± 0.23 and 2.96 ± 0.25 dpm/nmol in CP and N, respectively. No significant differences
between groups were found in the KIC-to-leucine SA ratios (CP:
0.83 ± 0.03; N: 0.78 ± 0.04). After the meal, the [14C]KIC SA decreased (P < 0.01 or less
vs. baseline) to 1.91 ± 0.12 and to 1.75 ± 0.17 dpm/nmol in
CP and N, respectively, and that of [14C]leucine to
2.18 ± 0.18 and to 2.24 ± 0.26 dpm/nmol,
respectively. The ratio of [14C]KIC to
[14C]leucine SA tended to increase (although
insignificantly) in the CP (to 0.88 ± 0.03, P > 0.1), whereas it did not change at all in the N (to 0.79 ± 0.05).
The slope of changes of albumin-bound leucine 14C SA
vs. time tended to decrease (although insignificantly) in the CP (from
0.138 ± 0.016 to 0.119 ± 0.025 dpm · µmol1 · min
1;
P = NS), whereas it did not change in the N (from
0.182 ± 0.029 to 0.191 ± 0.029 dpm · µmol
1 · min
1).
Substrate and hormone concentrations.
Plasma concentrations of the AAA phenylalanine and tyrosine were
40% greater (P < 0.01) in CP than in N in both the
basal and the postprandial states (Table
2). Methionine concentration in the CP
was also increased (P < 0.001; fasting state: 25 ± 2 vs. 15 ± 1; postprandial state: 42 ± 4 vs. 31 ± 1). Leucine and KIC concentrations were not different between the two
groups (Fig. 1, Table 2), although the sum of the BCAA concentrations
was slightly greater (by
15%, P < 0.05) in CP. The
BCAA-to-AAA (BCAA/AAA) ratio in the CP was
20% lower
(P < 0.05) than in N both in the fasted (CP: 3.25 ± 0.26; CS: 3.92 ± 0.2) and the fed states (3.23 ± 0.25 and 3.79 ± 0.18, respectively). The sum of total amino acids was
not different between the groups (Table 2).
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DISCUSSION |
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This study shows that ingestion of a mixed meal over 4 h did not acutely stimulate either albumin or whole body protein synthesis in compensated cirrhotic patients, in contrast to normal control subjects.
Several factors may account for these defects. Albumin and body protein synthesis are stimulated physiologically by meal ingestion and/or by hyperaminoacidemia (8, 9, 35, 37), the former also by insulin (8, 9). Both of these stimuli appeared to be ineffective in the cirrhotic patients postprandially. Hyperinsulinemia is a common finding in cirrhosis, and it may be due to hypersecretion and/or decreased hepatic extraction (27). The defective postprandial albumin synthesis despite hyperinsulinemia in cirrhosis is compatible with an insulin-resistant state involving also the hormone proteosynthetic hepatic effect. Such a resistance, in turn, may be secondary to alterations of liver architecture, circulation, and function, which are characteristic of this disease (6), including a shunt of insulin from the portal vein to the posthepatic circulation. A decreased first-pass splanchnic (liver) extraction of some dietary amino acids, such as phenylalanine (34), and the altered plasma profiles [i.e., the increased AAA concentrations and/or the decreased BCAA/AAA ratio (25)] might also have limited albumin synthesis. Among other possible alterations that are observed in cirrhosis (although not measured in this study), toxic effects by cytokines (2, 38), as well as a decreased insulin-like growth factor I (IGF-I) concentration (12), could also be considered. An interesting hypothesis is that albumin synthesis was already maximally stimulated in the postabsorptive state in the patients, thus preventing a further increase after the meal.
Because albumin concentration was normal in the patients despite the defective postprandial stimulation, a decreased albumin catabolism, helping to maintain a nearly normal balance between synthesis and degradation, cannot be excluded. Albumin fractional catabolism could be determined in vivo with the intravenous injection of iodine-labeled albumin (10). In this study, however, we did not perform such a test, mainly because of limitations in subjects' exposure to radioactive isotopes. Also, iodine kinetics may not correspond accurately to that of native albumin, rather reflecting a different pattern of albumin distribution between intra- and extravascular sites, i.e., its transcapillary escape (10), which may itself be altered in cirrhosis (19). On the other hand, by definition, synthesis must equal catabolism at steady state. Thus the decreased postprandial albumin FSR in the cirrhotic patients may also indicate a decreased fractional catabolic rate. As a matter of fact, the complex relationships between albumin synthesis and catabolism need to be further investigated.
Interestingly, a defective stimulation of whole body protein synthesis
in cirrhosis was previously reported by our group, which followed the
intravenous infusions of the branched-chain-enriched amino acids,
glucose, and insulin (36), and was in agreement with the
present findings. The defective albumin synthesis here observed could
account at least in part for the impaired postprandial whole body
protein synthesis. Indeed, in humans, albumin synthesis accounts for
30% of the increase of body protein synthesis after a meal
(8), and it may act as a carrier of protein-bound amino acids from visceral to peripheral organs, like muscle, postprandially (8, 10). Thus the impaired postprandial albumin synthesis might contribute to the reduced muscle mass often found in cirrhotic patients.
The defects in protein synthesis observed in the patients cannot be explained by their slightly greater body weight and LBM, because in obesity whole body protein synthesis was found to be normally stimulated by hyperaminoacidemia during insulin infusion (16). Furthermore, we found no correlation between either body weight or estimated LBM and albumin FSR in a large series of observations (unpublished observations). In regard to body composition, we acknowledge that neither Hume's method (14) nor DEXA (17) may be accurate enough to measure LBM in cirrhosis because of a possible shift of body water from intracellular to extracellular space(s) (10, 19), even in the absence of clinically and instrumentally demonstrable edema and ascites. Nevertheless, this uncertainty may affect only the absolute values of leucine kinetics but not albumin FSR or the relative changes vs. basal of both albumin and whole body protein kinetics.
A key issue is that of the validity of the use of KIC SA as the precursor pool of albumin synthesis also in cirrhosis. Theoretically, a decreased liver protein degradation in cirrhosis could increase the intrahepatic leucine SA locally and lead to an underestimation of albumin FSR, which could be interpreted as decreased synthesis. Only the measurement of intrahepatic leucyl tRNA could address this issue. However, such a measurement is clearly unfeasible in humans, for both ethical and technical reasons. As a matter of fact, limitations of current methods to measure albumin synthesis in vivo both in healthy and diseased states should be kept in mind.
Leucine Ra increased postprandially in both groups as a result of meal ingestion. Whether this increase was proportional to the leucine ingested with the meal cannot be established from our data, because no oral amino acid tracer was administered. For the same reason, neither first-pass leucine splanchnic uptake nor leucine Ra from endogenous protein breakdown could be accurately determined. However, these issues had been previously investigated by use of combined oral and intravenous isotope administrations (34).
Although either early or late anabolic effects might have been missed in the patients during the 4-h meal administration, these possibilities seem unlikely. Indeed, both whole body protein and albumin kinetics exhibit quite slow patterns (8, 9, 20, 37), i.e., it would be surprising if a brisk stimulation of protein synthesis occurred in cirrhosis early after the start of feeding and before the chosen sampling times. On the other hand, an impaired and/or delayed meal absorption cannot entirely be ruled out in the patients. Nevertheless, the near-elementary composition of the liquid meal, as well as the adequate increase of both amino acid concentrations and leucine oxidation in the patients postprandially, makes this possibility rather unlikely.
The patients' nearly normal fasting plasma leucine concentration is in agreement with previous (15, 18), although not all, reports (23, 24, 39). These variances might depend on the patients' weight, body composition, and clinical/nutritional status, as well as on insulin resistance and/or concentration, because BCAA levels are very sensitive to insulin action (9, 28, 35). Thus the patients' nearly normal BCAA levels may be accounted for by their mild fasting hyperinsulinemia.
In conclusion, a mixed meal ingestion did not acutely stimulate either albumin or whole body protein synthesis in stable cirrhotic patients as opposed to healthy control subjects. The mechanism(s) underlying these abnormalities need to be further investigated.
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ACKNOWLEDGEMENTS |
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We thank Prof. Antonio Piccoli for help in the statistical analysis.
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FOOTNOTES |
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This study was supported by Grant 9704295CT04 from the National Research Council (CNR) of Italy and by the Joint Project between CNR and Regione Veneto: Study of Energy Metabolism in the Elderly.
Address for reprint requests and other correspondence: P. Tessari, Dept. of Clinical and Experimental Medicine, Chair of Metabolism, Policlinico Universitario, via Giustiniani 2, 35128 Padova, Italy (E-mail: paolo.tessari{at}unipd.it).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00333.2001
Received 23 July 2001; accepted in final form 3 October 2001.
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