[Liver urea and glucose production in patients with alcohol-induced cirrhosis]. / Harnstoff- und Glucoseproduktion der Leber bei Patienten mit alkoholinduzierter Zirrhose.

OBJECTIVE: To use stable isotopes for the analysis of hepatic metabolic pathways (urea synthesis, glucose production), comparing them in alcoholic and normal liver, in order to obtain specific and quantitative information on metabolic functions of the liver. PATIENTS AND METHODS: Urea and glucose production as well as alanine metabolism in the liver were studied by means of stable isotopes in 7 males with alcoholic liver cirrhosis (mean age 46 +/- 4 years; height 173 +/- 5 cm; weight 73 +/- 3 kg) and 7 healthy male volunteers as controls (age 26 +/- 3 years; height 180 +/- 5 cm; weight 75 +/- 6 kg). The plasma concentrations of adrenaline, noradrenaline, insulin, glucagon and amino-acids were also measured. RESULTS: Urea synthesis was lower in the cirrhosis patients than in the controls (3.3 +/- 2.2 mumol/kg.min vs 4.8 +/- 0.9 mumol/kg.min, P < 0.05). But there were no differences in glucose production, alanine metabolism and adrenaline concentrations. The concentrations of glutamine, phenylalanine, tyrosine, insulin, glucagon and noradrenaline were significantly raised in the cirrhotic patients, those of valine and leucine significantly lower. CONCLUSIONS: Contrary to hepatic glucose production, which was within normal limits, urea synthesis was reduced by 30% in the cirrhotic patients. The use of stable isotopes provided detailed information on specific metabolic processes in cirrhotic livers.

Effects of epinephrine on glucose metabolism in patients with alcoholic cirrhosis.

The cirrhotic liver has been shown to be resistant to the actions of various glucoregulatory hormones. The objective of this study was to investigate the effects of epinephrine on hepatic glucose metabolism in cirrhotic patients. Thirteen cirrhotic and eight healthy subjects were studied. Hepatic glucose production and turnover of alanine and glycerol were measured using stable isotope technique before and during 70 and 150 minutes of epinephrine infusion (0.1 microgram/kg/min). beta-Adrenoreceptor binding sites and affinity in mononuclear leukocyte membranes also were determined. Hepatic glucose production and alanine turnover in normals significantly increased during epinephrine infusion, but did not change in cirrhotics. Glycerol turnover increased after 70 minutes of epinephrine infusion in both groups. Epinephrine induced a significant rise of high-affinity beta-adrenoreceptor binding sites in normals, yielding a significant correlation between hepatic glucose production and receptor density (r = .94, P < .0001). In cirrhotic patients, similar changes in the number of high-affinity beta-adrenoreceptors were observed, but no correlation with hepatic glucose production was detected. The cirrhotic liver did not respond normally to the stimulatory effect of epinephrine on hepatic glucose production. Because this blunted response was not related to changes of beta-adrenoreceptors, our findings suggest that epinephrine resistance in cirrhosis was caused by a postreceptor defect.

Glycerol metabolism in patients with alcohol-induced liver cirrhosis.

The clearance rate of glycerol has been found to be impaired in alcoholic liver disease. However it remains unclear, if this can be ascribed to a defect of hepatic gluconeogenesis. Thus, the purpose of this work was to investigate glycerol clearance and hepatic glucose production in patients with liver cirrhosis. 13 patients with alcohol-induced Child B cirrhosis and 8 healthy volunteers were studied. Rates of appearance (R(a)) of glycerol, glucose and alanine were determined using stable isotope techniques. In addition indocyanine green clearance (ICGC) and plasma substrate concentrations were measured. Clearance rates were calculated as R(a) divided by the corresponding substrate concentration. R(a) of glycerol in patients was not different from controls, but glycerol clearance was significantly reduced (29 +/- 3 vs. 41 +/- 4 ml/kg/min). No differences in R(a) of glucose and alanine and corresponding plasma concentrations were observed. ICGC in patients was about 35% lower than reference values. Diminished glycerol clearance in patients with liver cirrhosis was not due to impaired hepatic gluconeogenesis. Since glycerol is almost completely extracted by the liver decreased glycerol clearance possibly simply reflected compromised liver perfusion as seen by reduced ICGC.

Determination of glycerol turnover by stable-isotope technique in humans: a new [1,1,2,3,3-2H5]glycerol derivative for mass-spectrometry analysis.

The stable isotope-labeled [1,1,2,3,3-2H5]glycerol analyzed by negative-ion chemical ionization (NCI) mass spectrometry has been proven a valid tracer for studying glycerol kinetics in humans. Because of its high technical complexity, NCI mass spectrometry is available to only a few laboratories. Thus, the aim of our study was to create an alternative method for measuring [1,1,2,3,3-2H5]glycerol enrichment in plasma with a new derivative and positive-ion chemical ionization (PCI) mass spectrometry. It could be demonstrated that the trisacetyl[1,1,2,3,3-2H5]glycerol derivative was able to produce a fragment at m/z = 164 with sufficient intensity. Application of [1,1,2,3,3-2H5]glycerol in seven healthy volunteers resulted in reproducible measurements of basal glycerol turnover rates. The mean glycerol flux rate of 3.02 +/- 0.37 mumol.kg-1 body wt.min-1 after an overnight fast was similar to values reported from studies with comparable protocols. Physiological changes of lipolysis rates after 48 h of fasting followed by infusion of 4 mg.kg-1 body wt.min-1 glucose could also be adequately studied in one subject. Fast-induced elevated glycerol turnover at 7.56 mumol.kg-1 body wt.min-1, was substantially suppressed to 1.13 mumol.kg-1 body wt.min-1, when glucose was administered. The easily performed trisacetyl[1,1,2,3,3-2H5]glycerol derivative analyzed by PCI mass spectrometry is suitable for studying glycerol kinetics in humans.