Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease

Abstract

Background and Aim: Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways. Methods: We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men. Results: The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%, p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18–9.82, p=0.023). Conclusions: In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.

Identification and validation of cuproptosis-related genes in acetaminophen-induced liver injury using bioinformatics analysis and machine learning

“…Copper plays an essential cofactor in innate immunity and metabolism. Previous studies have demonstrated that copper deficiency is an independent risk factor for mortality in patients with advanced liver disease ( 41 ). Moreover, another study revealed that although copper levels are elevated in various liver fibrosis conditions, severe copper deficiency induced by tetrathiomolybdate exacerbates liver injury and fibrosis in rats ( 22 ).…”

The mechanism of copper homeostasis and its role in disease

“…Another of these liver diseases is acute-on-chronic liver failure, where the presence of an enlarged and unstable iron pool correlates with early mortality [43]. Moreover, copper deficiency is a recently discovered risk factor for infections and death before liver transplantation in patients with cirrhosis or portal hypertension [44]. In addition to lowering the CP acticity, copper deficiency reduces superoxide generation in neutrophils and macrophages, which directly impedes their bactericidal activity.…”

Exploring the Regulatory Effect of LPJZ-658 on Copper Deficiency Combined with Sugar-Induced MASLD in Middle-Aged Mice Based on Multi-Omics Analysis

“…Copper deficiency exacerbates hepatic fibrosis in bile duct-ligated rats, possibly mediated through reduced antioxidant defense and iron overload [15]. Notably, copper deficiency is relatively common in advanced cirrhosis and is associated with an increased risk of infection, a unique metabolic profile, and an increased risk of death before transplantation [16]. In addition, sugar intake further promotes the development of MASLD.…”