Copper Supplementation in Cirrhosis

Overview

End stage liver disease or cirrhosis is a major cause of mortality in the United States and the world. Other than targeting the underlying cause, such as alcohol cessation and antiviral therapy, very few medical treatments can change the natural history of cirrhosis. Malnutrition is one of the few potentially modifiable factors that have been associated with cirrhosis severity and poor prognosis. The transition metal copper (Cu) is an essential trace metal that must be acquired from diet. Its metabolism is primarily regulated by the liver in its role as a master regulator of nutrients. In 2019, the investigators reported that Cu deficiency defined by below normal serum or liver concentrations occurred in a wide range of liver disorders and was associated with a severe disease phenotype. Improvement in liver function was observed in 2 of the 3 patients who received Cu supplementation. In 2023, the investigators conducted a longitudinal cohort study utilizing clinical, serum and liver explant tissue data from 183 cirrhosis patients. The investigators showed that Cu deficiency was associated with 2-fold higher infection rate and a more than 3-fold increase in the risk of death compared to patients with normal Cu status. These preliminary findings and the well-established importance of Cu in human health prompted the investigators to design the current pilot randomized, placebo-controlled, crossover trial to determine the effect of Cu supplementation on Cu dependent biochemical changes, patient safety and patient reported outcomes in cirrhosis.

Approximately 41,000 people die annually of chronic liver disease (CLD) including liver cancer in the United States. Compared to other chronic diseases, patients with CLD have high rates of healthcare utilization and death. The annual cost of care for patients with cirrhosis, the most advanced stage of liver disease, is approximately $21 billion. While liver transplantation is a curative, albeit costly, treatment, there are far fewer donors than patients in need of liver transplants. Other than targeting the causes of cirrhosis, such as alcohol cessation and antiviral therapy, very few medical treatments can change the natural history of cirrhosis. Malnutrition is one of the few potentially modifiable factors that have been associated with cirrhosis severity and poor prognosis. Current guidelines in nutrition management focus on protein and calorie intake, with little consideration for trace metals, which have wide ranging physiological effects. The transition metal copper (Cu) is an essential trace metal that must be acquired from diet. Absorption, uptake, export and transport of Cu are tightly regulated because both too much and too little Cu can cause cell damage, compromised immune function and organ dysfunction. Systemic Cu metabolism is primarily regulated by the liver in its role as a master regulator of nutrients. Whole body Cu status is best estimated by its blood concentration. Depending on laboratory benchmarks and sex, the lower limit of normal serum Cu is between 70-80 g/dL where concentrations below this range likely reflect systemic Cu deficiency. In 2019, the investigators began an effort to better understand the role of Cu in liver disease and reported a series of patients who presented with unexplained low blood Cu concentrations. In this detailed report, Cu deficiency defined by below normal serum or liver concentrations occurred in a wide range of liver disorders and was associated with a severe disease phenotype. Improvement in liver function was observed in 2 of the 3 patients who received Cu supplementation. To further these preliminary observation, in 2023, the investigators conducted a longitudinal cohort study utilizing clinical, serum and liver explant tissue data from 183 cirrhosis patients. The investigators showed that Cu deficiency was associated with significantly higher infections rates (42% vs. 20%, p=0.01) and a more than 3-fold increase in the risk of death compared to patients with normal Cu status. These results provide concrete evidence that a complex, and potentially causal relationship exist between Cu status, compromised immune and metabolic functions and worse clinical outcomes in cirrhosis patients. These 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? To answer these questions, the investigators 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.