The rates of muscle protein breakdown, as estimated by the urinary excretion of 3-methylhistidine, were assessed in 30 cirrhotics and 15 controls on a strictly controlled diet. 3-Methylhistidine excretion was increased in cirrhotics irrespective of the etiology of the disease, and correlated with basal glucagon levels and with the insulin/glucagon ratio. In nine cirrhotics and nine age- and sex-matched controls, similar correlations were found between 3-methylhistidine and the areas under 24-hr glucagon or insulin/glucagon curves. A larger amount of 3-methylhistidine was excreted during the nighttime than during the daytime, when glucagon secretion was suppressed and the insulin/glucagon ratio was increased. It is concluded that muscle protein catabolism is increased in cirrhotics, possibly as a result of hyperglucagonemia or the reduced insulin/glucagon ratio. These data agree with the clinical observation of a progressive reduction in lean body mass which becomes evident in an advanced stage of the disease.
Neuropsychological status, as assessed by trailmaking test; plasma amino acids, and ammonia, were studied in 54 cirrhotics without clinical evidence of encephalopathy to determine the prevalence of subclinical mental dysfunction and its relationship to metabolic abnormalities. Control values for psychometric performance were established in 54 normal subjects matched for age, sex, educational level, and employment status. Of these subjects, 16 were also used as controls for fasting ammonia and plasma amino acids. Eighteen cirrhotics (33%) showed impaired performances of the psychometric test; free tryptophan and the ratio free tryptophan to neutral amino acids were increased in 37% and 62% of cases and correlated with the psychometric scores (r = 0.45 and r = 0.70, respectively). In eight cirrhotics with mild encephalopathy, psychometric and metabolic evaluations were repeated several times during the infusion of amino acid solutions rich in branch-chain amino acids. Again significant correlations were observed between the psychometric scores and plasma amino acids. We conclude that a considerable proportion of clinically normal cirrhotics have neuropsychological deficits. The severity of impairment may be related to the plasma amino acid imbalance, namely to an increased passage of tryptophan across the blood-brain barrier.
1. The urinary excretion of 3-methylhistidine and creatinine was measured in 15 controls and in two groups of 15 patients with liver cirrhosis, with and without severe muscle wasting. All subjects were on a meat-free diet. The values obtained were used to calculate the fractional catabolic rate of myofibrillar protein. 2. In patients without muscle wasting 3-methylhistidine excretion was high in the presence of normal urinary creatinine. The fractional breakdown rate was significantly increased as compared with that of controls. 3. In patients with severe muscle wasting 3-methylhistidine excretion was normal and urinary creatinine was remarkably reduced. The myofibrillar catabolic rate was further increased compared with that of controls and of the other group of patients. 4. 3-Methylhistidine and creatinine excretion allow a complete evaluation of myofibrillar protein degradation, which appears to be remarkably increased in cirrhotic patients. The relevance of increased myofibrillar protein turnover in muscle wasting of subjects with advanced cirrhosis remains to be determined.
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