Leucine metabolism in stable cirrhosis

Abstract

Alterations in protein and amino acid metabolism have been postulated to explain the frequent observations of muscle wasting and decreased plasma branched-chain amino acid concentrations in cirrhosis. In order to investigate the changes in protein metabolism, we have measured the rates of leucine turnover and oxidation in six stable, biopsy-proven cirrhotics and six age and sex-matched healthy control subjects after an overnight fast, using [1-¹³C]leucine tracer. Following a primed constant-rate infusion of [1-¹³C]leucine, the ¹³C enrichments of plasma leucine and expired CO₂ were used to estimate leucine turnover and oxidation, respectively. Fat-free body mass was estimated from the measurements of total body water as quantified by H₂[¹⁸O] tracer dilution. The rates of CO₂ production and oxygen consumption were measured hourly during the study period, using open-circuit respiratory calorimetry. Urinary urea, ammonia and total nitrogen excretion rates were quantified from timed urine samples. Even though the plasma leucine levels were lower in cirrhotics as compared with controls (100.5 ± 17.1 vs. 138.3 ± 20.4 μmoles per liter, mean ± S.D., p < 0.001), the rates of leucine turnover were not significantly different in the two groups (89.4 ± 19.0 vs. 87.8 ± 19.0 μmoles per kg ± hr). In contrast, the rates of leucine oxidation were significantly reduced in cirrhosis (8.1 ± 2.5 vs. 12.7 ± 3.1 μmoles per kg ± hr, p < 0.01). When all subjects were considered, the leucine oxidation rate was correlated with plasma leucine concentration (r = 0.62, p < 0.03). The plasma clearance rate of leucine was significantly increased in cirrhosis (903.5 ± 232.0 vs. 650.8 ± 164.4 ml per kg ± hr, p < 0.001), as was the fractional turnover rate of the free leucine pool (2.3 ± 0.5 vs. 1.6 ± 0.2% per min, p < 0.02). Calculated rates of protein degradation and protein synthesis were similar in the two groups. These alterations in protein metabolism were associated with elevated serum levels of insulin (12.5 ± 7.6 vs. 5.9 ± 1.1 μunits per ml, p < 0.03) and β-hydroxybutyrate (0.2 ± 0.6 vs. 0.13 ± 0.05 mM, p < 0.05). Although the basal metabolic rates were similar in the two groups, the respiratory quotients were reduced in cirrhosis (0.75 ± 0.01 vs. 0.84 ± 0.03, p < 0.001), suggesting an increased contribution of fat toward oxidative metabolism. Consistent with reduced leucine oxidation, urinary total and urea nitrogen were also decreased in cirrhosis (p < 0.01). Because total body water was similar in cirrhotics and controls (61.7 ± 6.1 vs. 58.4 ± 5.0% body weight), comparison of the data did not differ whether expressed per unit total body weight or per unit fat-free body mass. These data indicate plasma leucine concentrations may determine the rate of leucine oxidation. Consequently, the decreased rate of leucine oxidation in stable cirrhosis may be a consequence of decreased substrate availability. Although hyperinsulinemia was associated with decreased plasma leucine levels in cirrhosis, there was no significant difference in leucine or protein turnover between the cirrhosis and control groups.