Copper Supplementation 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.

Inclusion criteria

• Adult patients age 18 or older with confirmed diagnosis of cirrhosis based on clinical history, exam, imaging, laboratory or histological criteria;
• Cirrhosis patients whose serum or plasma Cu are below the normal range (80-155 ug/dL for women and 70-140 ug/dL for men);
• Cirrhosis patients whose serum or plasma Cu are in the normal range but exhibit at least one clinical feature that has been associated with Cu deficiency. These include history of infections, unexplained anemia, severe leukopenia, iron overload, unexplained neurological symptoms such as ataxia or myelopathy, coagulopathy with spontaneous bleeding.

Patients must meet inclusion criteria 1 AND 2, or 1 AND 3 in order to be considered for the trial

Exclusion criteria

• Patients with Wilson disease, cholestatic liver diseases including primary biliary cholangitis and primary sclerosing cholangitis, all of which are associated with Cu overload;
• Patients with fulminant hepatic failure;
• Renal failure with a creatinine clearance <25 ml/minute;
• Hepatic encephalopathy more than grade 2 (Hepatic Encephalopathy in Chronic Liver Disease, 2014);
• MELD score >25 to minimize subject dropout due to been too ill;
• Serious non-liver related medical illnesses such as cardiopulmonary and renal diseases and non-liver malignancies;
• Active alcohol use;
• Pregnancy