Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis

Abstract

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.

Functional Microbiomics Reveals Alterations of the Gut Microbiome and Host Co‐Metabolism in Patients With Alcoholic Hepatitis

“…As a result of two opposite effects, decreased capacity for urea synthesis has been reported in patients with alcoholic hepatitis. (33) Consistently, a decrease of urea was observed in the serum samples of patients with alcoholic hepatitis compared with controls in our patient cohort, which is likely due to the decrease in hepatic urea synthesis. In line with the decrease of hepatic urea synthesis in the cohort of patients with alcoholic hepatitis, the contribution of microbial urea synthesis to the total urea pool might increase.…”

“…(29)(30)(31)(32) The capacity of urea synthesis is decreased in patients with compromised liver function but increases in patients with inflammation. (33) Interestingly, both mechanisms are involved in alcoholic hepatitis. As a result of two opposite effects, decreased capacity for urea synthesis has been reported in patients with alcoholic hepatitis.…”

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“…The reduced amino acid degradation could result in less intramitochondrial ammonia being available for the already downregulated urea cycle feeder genes, which would further compromise the running of the urea cycle . Such decreased urea synthesis capacity and resulting hyperammonaemia has earlier been described in cirrhosis and in acute liver failure, in these conditions as a consequence of loss of functional liver mass, whereas the problem in NAFLD seems to be specifically rooted in the hepatocyte fat accumulation.…”

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