Copper Supplementation in Cirrhosis

A Pilot Randomized Controlled Trial to Determine the Biochemical Effect, Safety and Patient Reported Outcomes of Copper Supplementation in Patients With Cirrhosis

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.

Study Overview

• Status: Recruiting
• Conditions: Fibrosis; Cirrhosis; Infection; Chronic Liver Disease
• Intervention / Treatment: Dietary supplement: Copper Gluconate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laura Sissons-Ross; Phone Number: 206-616-0397; Email: lsissons@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington Medical Center
      • Principal Investigator: Lei Yu, MD
      • Contact: Shukriyah Samoun, BS; Phone Number: 2065433220; Email: shukrs@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult patients age 18 or older with confirmed diagnosis of cirrhosis based on clinical history, exam, imaging, laboratory or histological criteria;
2. 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);
3. 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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Copper supplementation 1st arm; copper supplementation first, washout, then placebo	Dietary supplement: Copper Gluconate; Oral copper gluconate 4 mg daily
Experimental: Placebo first arm; Placebo first, washout, then copper supplementation	Dietary supplement: Copper Gluconate; Oral copper gluconate 4 mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma copper (Cu) concentration	The primary endpoint is the mean change in plasma Cu concentration between baseline and each intervention period	From randomization to 1. end 6-week; 2. end of 9-week; 3. end of 15 week. First 6 week is intervention period 1 (either copper or placebo); followed by a 3-week washout period; followed by another 6-week intervention period (either placebo or copper).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of functional Copper (Cu) status	Plasma ceruloplasmin concentration and activity	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper)
Biomarkers of functional copper status	Plasma diamine oxidase concentration and activity	Time Frame: From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or
Biomarker of functional copper status	Neutrophil and PBMC oxidative burst activity	Time Frame: From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or
Biomarker of functional copper status	PBMC superoxide dismutase (CCS) mRNA expression	From randomization to 1. end 6-week; 2. end of 9-week; 3. end of 15 week. First 6 week is intervention period 1 (either copper or placebo); followed by a 3-week washout period; followed by another 6-week intervention period (either placebo or copper)
Biomarker of functional copper status	Platelet cytochrome-C oxidase (COX) activity	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper)
Safety measures	Patient death before liver transplantation	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper)
Safety measures	Change in liver function based on MELD (maximum 40, high school worse liver function) and CTP score (5 to 15, higher school worse liver function)	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper)
Safety measures	Incidence of hospital admission from infection or bleeding	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper)
Safety measure	Plasma ratio of reduced to oxidized glutathione (GSH/GSSG)	Time Frame: From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or
Patient reported outcomes	Change in Chronic Liver Disease Questionnaire (CLDQ)	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper)
Patient reported outcomes	Short form health survey	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper).
Functional and nutritional status	Liver frailty index based on grip strength, chair stands and balance	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper).
Functional and nutritional status	triceps skin fold in centimeters	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper).
Functional and nutritional status	Mid-arm circumference in centimeter	From randomization to 1) end 6-week; 2) end of 9-week; 3) end of 15 week. First 6 week is intervention period 1 (either copper or placebo), followed by a 3-week washout period, followed by another 6-week intervention period (either placebo or copper).

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alaska Fairbanks
• Investigators: Principal Investigator: Lei Yu, MD, University of Washington

Publications and helpful links

General Publications

• Uauy R, Olivares M, Gonzalez M. Essentiality of copper in humans. Am J Clin Nutr. 1998 May;67(5 Suppl):952S-959S. doi: 10.1093/ajcn/67.5.952S.
• Dhanda A, Atkinson S, Vergis N, Enki D, Fisher A, Clough R, Cramp M, Thursz M. Trace element deficiency is highly prevalent and associated with infection and mortality in patients with alcoholic hepatitis. Aliment Pharmacol Ther. 2020 Aug;52(3):537-544. doi: 10.1111/apt.15880. Epub 2020 Jun 23.
• Yu L, Liou IW, Biggins SW, Yeh M, Jalikis F, Chan LN, Burkhead J. Copper Deficiency in Liver Diseases: A Case Series and Pathophysiological Considerations. Hepatol Commun. 2019 Jun 26;3(8):1159-1165. doi: 10.1002/hep4.1393. eCollection 2019 Aug.
• Yu L, Yousuf S, Yousuf S, Yeh J, Biggins SW, Morishima C, Shyu I, O'Shea-Stone G, Eilers B, Waldum A, Copie V, Burkhead J. Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease. Hepatol Commun. 2023 Feb 20;7(3):e0076. doi: 10.1097/HC9.0000000000000076. eCollection 2023 Mar 1.

Study record dates

Study Major Dates

• Study Start (Estimated): March 15, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 2, 2026
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: malnutrition; cirrhosis; copper
• Additional Relevant MeSH Terms: Pathologic Processes; Nutrition Disorders; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Malnutrition; Fibrosis; Infections; Organic Chemicals; Carbohydrates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Gluconates
• Other Study ID Numbers: STUDY00023686; 1R01DK142802-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: For patient confidentiality, we likely will not share individual data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No