Unresponsiveness of hepatic nitrogen metabolism to glucagon infusion in patients with cirrhosis: Dependence on liver cell failure

Fabbri, Andrea; Marchesini, Giulio; Bianchi, Giampaolo; Bugianesi, Elisabetta; Bortoluzzi, L; Zol, Marco; Pis, Emilio

doi:10.1002/hep.1840180106

Cited by 17 publications

(6 citation statements)

References 30 publications

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“…The results of the simulated bleed study clearly show that the liver in the cirrhotic patient is unable to increase ammonia uptake or urea production following a simulated bleed. This is in agreement with results obtained by Fabbri et al, 43 who reported that urea synthesis in cirrhotic patients is refractory to stimulation by alanine, a known strong stimulus for urea synthesis. In patients with cirrhosis, muscle is the major ammonia-removing organ in the body.…”

Section: Ammonia Removal During a (Simulated) Ugi Bleedsupporting

confidence: 93%

The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis

et al. 2003

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Upper gastrointestinal (UGI) bleeding in cirrhosis is associated with enhanced ammoniagenesis, the site of which is thought to be the colon. The aims of this study were to evaluate interorgan metabolism of ammonia following an UGI bleed in patients with cirrhosis. Study 1: UGI bleed was simulated in 8 patients with cirrhosis and a transjugular intrahepatic portasystemic stent-shunt (TIPSS) by intragastric infusion of an amino acid solution that mimics the hemoglobin molecule. We sampled blood from the femoral artery and a femoral, renal, portal, and hepatic vein for 4 hours during the simulated bleed and measured plasma flows across these organs. Study 2: In 9 cirrhotic patients with an acute UGI bleed that underwent TIPSS insertion, blood was sampled from an artery and a hepatic, renal, and portal vein, and plasma flows were measured. Study 1: During the simulated bleed, arterial concentrations of ammonia increased significantly (P ‫؍‬ .002). There was no change in ammonia production from the portal drained viscera, but renal ammonia production increased 6-fold (P ‫؍‬ .008). In contrast to an unchanged ammonia removal by the liver, a significant increase in muscle ammonia removal was observed. Study 2: In patients with an acute UGI bleed, ammonia was only produced by the kidneys (572 [184] nmol/kg bw/min) and not by the splanchnic area (؊121 [87] nmol/kg bw/min). In conclusion, enhanced renal ammonia release has an important role in the hyperammonemia that follows an UGI bleed in patients with cirrhosis. During this hyperammonemic state, muscle is the major site of ammonia removal.

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Section: Ammonia Removal During a (Simulated) Ugi Bleedsupporting

confidence: 93%

The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis

et al. 2003

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“…34,35 Theoretically, the improvement in FHNC might also transport in the liver and through up-regulation of urea cycle enzymes, 34,35 but its effects are blunted or absent be the effect of spontaneously fluctuating disease activity and/or alcohol abstinence in alcoholic cirrhosis, in in cirrhosis. 14,36 In the present study, zinc supplementation was associated with an unexpected, systematic which liver function considerably improves in the first 1 to 2 years after alcohol abstinence. 43 However, no inhibitory effect on basal and alanine-stimulated glucagon concentration, excluding any glucagon-mediated specific effect of alcohol was proven, because FHNC increased in all subjects in the experimental group, effect on hepatic nitrogen clearance.…”

Section: Discussionmentioning

confidence: 84%

“…Urea-N in plasma and urine was urine and accumulation of urea-N in the urea space, assumed to equal total body water (TBW), as 14 measured by the urease Berthelot method. 23 Alanine was measured enzymatically, 24 and total a-amino-N was mea-…”

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confidence: 99%

Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis

et al. 1996

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Zinc deficiency is common in cirrhosis and has been tent is common in patients with advanced cirrhosis, involved in the altered nitrogen metabolism. In this particularly of alcohol origin, 2 but the biochemical basis study, we measured the effects of zinc supplementation for zinc deficiency is still unknown. Several factors, on the dynamics of amino acid-derived urea synthesis such as poor dietary intake, impaired intestinal absorp-in cirrhosis with mild or latent encephalopathy. The he-tion, and excessive urinary losses may be responsible patic conversion of amino acids into urea was studied in for reduced whole-body zinc content. 3 eight patients with advanced cirrhosis under controled The importance of zinc deficiency in precipitating ep-conditions of substrate availability (continuous alanine isodes of hepatic encephalopathy is a matter of discus-infusion), before and after 3-month oral zinc sulfate sup-sion. In a single patient with cirrhosis and severe recur-plementation (600 mg/d). Eight more patients, matched rent hepatic encephalopathy, zinc levels after zinc for hepatocellular failure and encephalopathy, served as controls. Plasma zinc levels were reduced in all pa-supplementation and artificially induced zinc defi-tients and returned to normal after oral zinc. The ala-ciency correlated closely with mental state and electro-nine-stimulated urea nitrogen synthesis rate in relation encephalography tracings. 4 In a randomized double-to a-amino-N concentration-the functional hepatic ni-blind trial, zinc sulfate oral supplements increased to trogen clearance-increased by 25% after zinc supple-normal plasma zinc levels of cirrhotic patients and sig-mentation, i.e., more urea was produced at any a-amino-nificantly improved mild encephalopathy of the chronic N concentration. Basal and alanine-induced glucagon type. 5 During treatment, ammonia levels decreased, decreased by 50%, and the ammonia response to alanine and plasma urea concentration increased. The results decreased by 30%. Psychometric tests improved, as did routine and dynamic liver function tests and the Child-were not confirmed in a short-term crossover study Pugh score. Also, the plasma concentration of lipid per-with zinc acetate supplements, which failed to normal-oxides was reduced by zinc. No significant changes were ize plasma zinc levels. 6 Also episodes of acute encepha-observed in the control group. Our data indicate that lopathy after gastrointestinal hemorrhage have been long-term oral zinc speeds up the kinetics of urea forma-successfully treated with zinc. 7 In cirrhotic rats, zinc tion from amino acids and ammonia. Changes in the hor-supplementation was shown to increase the hepatic ac-monal drive and/or the antioxidant activity of zinc might tivity of ornithine transcarbamoylase, a key-enzyme of be involved in the general improvement in liver func-urea cycle. 8 This was accompanied by increased urea tion, whereas the beneficial effects on encephalopathy might stem from decreased ammonia. (HEPATOLOGY formation and decreased ammonia l...

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“…Notably, the FHNC values that we measured in the severe AH patients were as low as those previously reported only in patients with acute liver failure of a non-alcoholic etiology [ 39 ]. Such low values have not been reported in even advanced cirrhosis patients [ 21 , 40 , 41 ]. Further, some of our AH patients did not have cirrhosis, and the presence of cirrhosis did not distinguish the particular values of FHNC.…”

Section: Discussionmentioning

confidence: 90%

Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis

et al. 2016

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Background and AimData on quantitative metabolic liver functions in the life-threatening disease alcoholic hepatitis are scarce. Urea synthesis is an essential metabolic liver function that plays a key regulatory role in nitrogen homeostasis. The urea synthesis capacity decreases in patients with compromised liver function, whereas it increases in patients with inflammation. Alcoholic hepatitis involves both mechanisms, but how these opposite effects are balanced remains unclear. Our aim was to investigate how alcoholic hepatitis affects the capacity for urea synthesis. We related these findings to another measure of metabolic liver function, the galactose elimination capacity (GEC), as well as to clinical disease severity.MethodsWe included 20 patients with alcoholic hepatitis and 7 healthy controls. The urea synthesis capacity was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the blood α-amino nitrogen concentration and urea nitrogen synthesis rate during alanine infusion. The GEC was determined using blood concentration decay curves after intravenous bolus injection of galactose. Clinical disease severity was assessed by the Glasgow Alcoholic Hepatitis Score and Model for End-Stage Liver Disease (MELD) score.ResultsThe FHNC was markedly decreased in the alcoholic hepatitis patients compared with the healthy controls (7.2±4.9 L/h vs. 37.4±6.8 L/h, P<0.01), and the largest decrease was observed in those with severe alcoholic hepatitis (4.9±3.6 L/h vs. 9.9±4.9 L/h, P<0.05). The GEC was less markedly reduced than the FHNC. A negative correlation was detected between the FHNC and MELD score (rho = -0.49, P<0.05).ConclusionsAlcoholic hepatitis markedly decreases the urea synthesis capacity. This decrease is associated with an increase in clinical disease severity. Thus, the metabolic failure in alcoholic hepatitis prevails such that the liver cannot adequately perform the metabolic up-regulation observed in other stressful states, including extrahepatic inflammation, which may contribute to the patients’ poor prognosis.

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Unresponsiveness of hepatic nitrogen metabolism to glucagon infusion in patients with cirrhosis: Dependence on liver cell failure

Cited by 17 publications

References 30 publications

The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis

The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis

Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis

Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis

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