Loss, amplification or mistiming of the daily rhythms of metabolic markers in patients with cirrhosis.

Background & Aims: The aim of the present study was to evaluate the temporal dynamics of metabolites in patients with cirrhosis using hourly plasma samples collected over a full 24-hour cycle in 17 outpatients with cirrhosis of varying severity (9 males, 58 [39-77] years, 12 compensated/5 decompensated) and 9 matched healthy controls (8 males, 60 [38-84] years). Methods: A total of 142 metabolites were quantified by targeted metabolomics, including 11 acylcarnitines, 19 amino acids, 9 biogenic amines, 88 glycerophospholipids, 14 sphingolipids, 1 monosaccharide and the circadian hormones melatonin and cortisol. Multivariate analyses were performed using PCA (principal component analysis) and OPLS-DA (orthogonal partial least squares-discriminant analysis). To assess 24-hour rhythmicity, a linear mixed-effect cosinor method was applied, providing peak times and amplitudes. Results: PCA and OPLS-DA revealed clear differences between groups. The four metabolites which best distinguished the groups were the glycerophospholipids P32:0 and PC O-32:1, the amino acid tyrosine and the biogenic amine methionine sulfoxide (VIP scores 1.59-1.62), all of which were increased in decompensated patients. Significant 24-hour rhythms were detected in 46% of metabolites and both circadian hormones in healthy volunteers, compared with 16% of metabolites and both hormones in patients. A significant phase advance was observed for acylcarnitines, while amino acids, glycerophospholipids, and both circadian hormones exhibited phase delays in patients relative to healthy controls. Additionally, some rhythmic metabolites showed progressively increased amplitudes in patients, indicating larger oscillations over the 24 hours. Conclusions: Major abnormalities in both absolute plasma metabolite concentrations and their daily rhythm were observed in a small but well characterised group of outpatients with cirrhosis of varying severity. Impact and implications: This study demonstrates significant disruptions in the daily rhythms of plasma metabolites in patients with cirrhosis that parallel disease severity. Although the underlying mechanisms and direct clinical consequences of these rhythm disturbances require further investigation, their potential long-term effects are likely to be important, particularly in the context of metabolic and nutritional health in this patient population. These findings highlight the need to consider temporal dynamics in both the assessment and management of cirrhosis and may inform future strategies for chronotherapy, dietary interventions, and personalized care.