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Copper is an essential micronutrient that is found in foods such as dark chocolate, almonds, and liver. Dietary copper intake is approximately 1 to 2 mg per day. The daily requirement for copper is approximately 0.75 mg.  Copper is an important cofactor for many enzymes, including cytochrome C oxidase (cellular respiration), ceruloplasmin (iron oxidation), tyrosinase (pigment formation), monoamine oxidate (neurotransmitter biosynthesis), superoxide dismutase (antioxidant defense), and lysyl oxidase (connective tissue formation).

Copper is primarily absorbed through the gastrointestinal tract and excreted by the biliary tract. Normally, daily copper absorption and excretion are balanced. Copper is predominantly absorbed in the duodenum. Shortly after absorption, copper is bound to albumin and stored in hepatocytes. Hepatocytes are capable of rapidly increasing biliary excretion of copper in response to increases in systemic copper load. Therefore, hepatic copper accumulation rarely occurs under physiological condition.

Ceruloplasmin is a ferroxidase enzyme that plays an essential role in iron metabolism. It is synthesized in hepatocytes as apo-ceruloplasmin and secreted into plasma after binding copper to form holo-ceruloplasmin. More than 95% of plasma copper is bound to ceruloplasmin. Failure to bind copper results in loss of enzymatic activity and rapid degradation. For this reason, serum ceruloplasmin concentration is a useful indicator of copper status.

Neurologic manifestations of copper deficiency include myelopathy, polyneuropathy, optic neuropathy, myopathy, and motor neuron disease. Copper deficiency myelopathy is characterized by sensory loss, ataxia, weakness that is more severe in the legs than in the arms, and hyperreflexia. Copper deficiency has also been associated with hematologic abnormalities including anemia, neutropenia, and in rare cases, thrombocytopenia. Anemia may be related to the reduced level and function of copper-dependent enzymes, including ceruloplasmin, that affect iron transport and metabolism.

The most common causes of copper deficiency are malabsorption and excessive zinc ingestion. Roux-en-Y gastric bypass accounts for about half of copper deficiency cases. Other types of malabsorption that have been associated with copper deficiency include cystic fibrosis, celiac disease and inflammatory bowel disease. Copper and zinc are competitively absorbed by enterocytes. Excessive zinc may arise from ingestion dietary supplements, ingestion of denture cream or chronic hemodialysis.

Valproic acid has been associated with lower blood copper levels, but the mechanism is unknown. Copper deficiency is the hallmark of Menkes disease, which is congenital x-linked disorder. It is caused by a mutation in the ATP7A gene, which codes for the transport protein mediating copper uptake from the intestine. Affected patients develop severe copper deficiency with progressive neurologic deterioration and death during early childhood.

Wilson disease, also known as hepatolenticular degeneration, is an autosomal recessive disorder that is caused by a mutation in the ATP7B gene that results in a deficiency of ATPase, an enzyme needed to transport copper from the liver to bile. As a result, copper accumulates first in the liver and then in brain, kidneys, bones, and corneas. Wilson disease affects approximately 1 in 30,000 people worldwide, with a carrier frequency of approximately 1 in 90 individuals. Patients with Wilson’s disease may present with chronic liver disease, acute liver failure, hemolysis, and psychiatric or neurologic manifestations.

In patients with either symptomatic or asymptomatic Wilson’s disease, serum copper level is usually low. Copper levels are decreased in proportion to ceruloplasmin. However, serum copper measurement by itself is not very useful and is sometimes confusing. Levels may vary during the course of the disease. When the patient has hemolysis with or without fulminant presentation, the serum copper level can be substantially elevated. Patients with Wilson’s disease have increased copper in urine and significantly elevated iron in hepatocytes as determined by liver biopsy.

The hallmark of copper deficiency is a low blood copper level; 45% of patients have a level lower than 0.10 μg per mL (1.57 μmol per L). Reference range is 0.75 to 1.45 μg per mL (11.80 to 22.81 μmol per L). Ceruloplasmin is also decreased below the reference range of 20 to 60 mg/dL in patients with copper deficiency. Although ceruloplasmin is still produced by hepatocytes, it exists as apoenzyme that lacks copper and is rapidly degraded.

The amount of copper excreted in the urine in a 24-hour period is helpful for diagnosing Wilson’s Disease and for monitoring treatment. The normal range for 24-hour urinary copper is 15-60 ug/day. Urine copper levels greater than 100 ug/day are generally diagnostic for Wilson’s Disease.

Although 24-hour urinary copper excretion is almost invariably increased in patients with WD, elevated copper in the urine can be seen in other cholestatic disorders. 24-hour urinary copper assays may not be reliable if a patient has received chelation therapy. Urinary copper is elevated during and for a few days after the treatment, but rebound lowering of urine copper levels below basal levels has been observed in many WD patients.


Bowley MP, et al. Case 35-2017 — A 57-Year-Old Woman with Hypoesthesia and Weakness in the Legs and Arms, N Engl J Med 2017;377:1977-84. 

Olson KR, et al. Case 2-2017 — An 18-Year-Old Woman with Acute Liver Failure. N Engl J Med 2017; 376:268-278

Gu YH, Kodama H, Du SL, et al: Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clin Genet 2003;64[6]:479-484

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