A pilot randomized controlled trial to determine the biochemical effect, safety and patient reported outcomes of copper supplementation in cirrhosis

Project Summary: The overall premise of this research is that copper (Cu) status is a previously under-recognized and potentially modifiable risk factor in cirrhosis, the most advanced stage of chronic liver disease. In the United States, chronic liver disease affects 4.5 million people and accounts for over 41,000 deaths per year. Cirrhosis requires high rates of healthcare utilization compared to other diseases with an annual cost of approximately $21 billion. Malnutrition is one of the few modifiable factors that have been associated with poor prognosis. Current guidelines in nutritional intervention focus on protein and calorie intake, and give little consideration to trace elements, which have wide ranging physiological effects. Cu deficiency in the absence of liver disease compromises Cu dependent enzyme functions which can cause iron overload, tissue fibrosis and susceptibility to infections – pathologies also observed in cirrhosis. Our recent large cohort study identified Cu deficient cirrhosis patients, as defined by low serum Cu concentrations, had higher infection rates and a 3.4-fold increased risk of death compared to patients with normal Cu levels. Our preliminary findings and the well- established importance of Cu in human health raise several important questions: Does reduced circulating Cu, the standard definition of Cu deficiency in the general population, similarly reflect a deficiency state in cirrhosis? Is the higher infection and mortality risk observed among patients with low serum Cu mediated by Cu dependent enzymes and immune cells? Is reduced circulating Cu a secondary response in cirrhosis, therefore should be “left alone,” or should patients receive Cu supplementation in order to improve functional Cu store and its associated physiological functions? In an attempt to answer these questions, we designed a pilot randomized, placebo-controlled, crossover trial to determine the effect of Cu supplementation on Cu dependent biochemical changes, patient safety and patient reported outcomes.