Copper - physio

Absorbed via specific intestinal transporter

Circulates bound to ceruloplasmin

Enzyme cofactor (superoxide dismutase, cytochrome

oxidase, and enzymes involved in iron metabolism and

connective tissue formation)
Dietary sources
Vegetables, grains, nuts, liver, margarine, legumes, corn

oil
The highest content of copper is found in liver (20 to 180
mg/kg versus 1 to 2.6 mg/kg in white bread and 0.02 to
0.08 mg/kg in cow's milk).
The newborn term infant contains approximately 12 mg.
Breast milk contains relatively little copper.

Early in lactation breast milk contains up to 0.7 mg/L

copper but this rapidly falls to 0.2 mg/L (below

recommended copper intake by the WHO).
During this period, any shortfall in copper intake can be
met by mobilizing liver copper stores.
Metabolism
Absorbed in the proximal small intestine,
transported to the liver loosely bound to albumin and
plasma amino acids.
Copper transporter (transcuprin) also may be involved.

Most copper is taken up by the liver on first pass, &

Is incorporated into the copper-containing protein

ceruloplasmin - transport copper from the liver to

peripheral tissues.
Ceruloplasmin serves as a plasma feroxidase, converting

iron to a valence that can be bound by plasma transferrin.

Metallothionein, synthesized in the liver, may act as a

copper storage protein.

50 % of copper is excreted in the

50% excreted through other gastrointestinal secretions.

Renal losses only account for 5 to 15% of the daily

excretion.
Dietary reference intake — 
RDA for copper is 340 mcg daily for young children.

The UL is 1000 mcg daily in young children and 10,000

mcg daily for adults

Biological role – component of enzymes…
Zinc-copper superoxide dismutase (antioxidant

defense)
Dopamine mono-oxygenase (neurotransmitter

synthesis)
Lysyl oxidase (collagen cross-linking, bone formation)
Ceruloplasmin (copper transporter and ferroxidase)
Cytochrome c oxidase (electron transport)
Factor V (thrombosis)
Tyrosinase (melatonin production)
These cupro-enzymes help to explain some of the
clinical features of severe copper deficiency, including
lack of skin pigmentation (decreased dopamine beta-

hydrolase),
weakness (decreased cytochrome c), and

bleeding disorders (decreased factor V)

 Copper def…
Risk factors
premature infants receiving milk formulas,

patients with chronic diarrhea, and

chronic peritoneal dialysis.

high doses of zinc (eg, from prolonged ingestion of zinc

supplements, or zinc-containing coins)

Copper & zinc are competitively absorbed from the jejunum

Gastric surgery.
Prior foregut surgery.

Roux-en-Y gastric

malabsorptive gastrointestinal surgery

 Clinical …
Two heritable diseases are caused by inborn errors of

copper metabolism:
Wilson's disease is a disorder of copper excretion 

copper toxicity,
Menkes disease is a disorder of copper uptake from the

intestine copper deficiency.

 Clinical…
Deficiency – c/f
fragile, abnormally-formed hair,

depigmentation of the skin,

muscle weakness,

edema, and hepatosplenomegaly,

Osteoporosis,

Neurologic manifestations - ataxia, neuropathy and

cognitive deficits that can mimic vitamin B12 deficiency
 Clinical…
Hematologic – microcytic hypochromic anemia,

neutropenia, thrombocytopenia, edema, and

hepatosplenomegaly.
If iron supplements are given for the anemia  worsen

copper deficiency because excess iron competes with

copper and decreases net copper absorption
Other laboratory findings include low
plasma copper,
ceruloplasmin,
erythrocyte copper-zinc superoxide levels, and
diminished 24-hour urinary copper excretion.

Treatment for copper deficiency consists of

supplementation, and correction of the underlying cause
of the deficiency, if possible.
 Menkes disease
also known as Menkes kinky hair syndrome, is a

congenital x-linked genetic disorder with an incidence of

about 1:100,000 live births.
It is caused by a mutation of the transport protein

mediating copper uptake from the intestine 

severe copper deficiency with progressive

neurodegeneration & death during early childhood.

This gene is closely related to the gene responsible for

copper overload in Wilson's disease.

Menkes disease – C/fs
are severe and occur during early infancy.
developmental delay, which usually becomes apparent
during early infancy,
progressive neurologic symptoms.

Physical features include peculiar "kinky" hair, growth

retardation, hypopigmentation of the skin, and bony

abnormalities, including osteoporosis and spur
formation.
Menkes disease – C/fs
The severity of the symptoms and lifespan are variable.

Treatment consists of parenteral copper-histidine

complex, which is not consistently effective.

Toxicity - Clinical features
Acute copper poisoning
gastrointestinal symptoms, including abdominal pain,

diarrhea, and vomiting.

In more severe forms  cardiac and renal failure, hepatic

necrosis, encephalopathy, and ultimately death .

It can result from accidental consumption by children,

contaminated water sources, suicide attempts, and topical

creams for burn treatment which contain copper salts
Ceruloplasmin (like ferritin) is an acute phase reactant,

so serum copper and ceruloplasmin levels are increased

in inflammatory processes, pregnancy, coronary artery
disease, diabetes, malignancies, and renal failure
Wilson's disease - (hepatolenticular degeneration)
Autosomal recessive disorder characterized by excessive
copper accumulation
caused by a mutation in a copper-ATPase enzyme
closely related to the Menkes disease gene product.
Excessive copper is deposited in many tissues and leads

to cardiac dysfunction, liver cirrhosis, pancreatic

dysfunction (diabetes mellitus), and neurological
abnormalities.
The hepatic injury is caused by excess copper which acts
as a pro-oxidant and promotes the generation of free
radicals.
Once cirrhosis occurs, copper leaks into the plasma,
accumulates in and damages other tissues.
The incorporation of copper into ceruloplasmin is also
impaired  decreased serum ceruloplasmin
concentrations present in most patients with Wilson's
disease.
PATHOLOGY 
The earliest lesion in Wilson's disease occurs in the liver.
fatty infiltration within hepatocytes,
glycogen inclusions within nuclei, and
portal fibrosis.
As the disease progresses, frank hepatocellular necrosis
occurs and the histologic lesion resembles that of
autoimmune chronic hepatitis.
There is portal inflammation and fibrosis, piecemeal
necrosis, with marked swelling and necrosis of periportal
hepatocytes and eventually frank cirrhosis.
Intrahepatic inclusions similar to Mallory bodies may be
seen in periportal areas.
Clinical manifestations
arise as hepatic and extrahepatic copper deposition
progresses.
Rare before age 6 and almost always present before the
age of 30, but
Described in those as young as age 3 and patients
presenting in their seventies.
Differences in mutations & penetrance as well as
extragenic factors.
Forms of Wilsonian hepatic disease include
asymptomatic hepatomegaly (with or without
splenomegaly),
subacute or chronic hepatitis, and
acute hepatic failure (with or without hemolytic
anemia).
Cryptogenic cirrhosis, portal hypertension, ascites,
edema, variceal bleeding, or other effects of hepatic
dysfunction (delayed puberty, amenorrhea, coagulation
defect) can be manifestations of Wilson disease
The younger the patient, the more likely hepatic
involvement will be the predominant manifestation.
Girls are 3 times more likely than boys to present
with acute hepatic failure.
After 20 yr of age, neurologic symptoms predominate
Kayser-Fleischer (K-F) ring.
There is a brown discoloration at the
outer margin of the cornea because of
the deposition of copper in Descemet's
membrane.
Here it is clearly seen against the light
green iris
Coombs-negative hemolytic anemia may be an initial
manifestation, possibly related to the release of large
amounts of copper from damaged hepatocytes;
is usually fatal without transplantation.
During hemolytic episodes, urinary copper excretion
and serum copper levels (not ceruloplasmin bound)
are markedly elevated.
Manifestations of renal Fanconi syndrome and
progressive renal failure with alterations in tubular
transport of amino acids, glucose, and uric acid may be
present.
Unusual manifestations include arthritis, infertility or
recurrent miscarriages, cardiomyopathy, and
endocrinopathies (hypoparathyroidism).
Treatment for Wilson's disease consists of avoidance of
high copper foods and copper chelation.
In early stages, pharmacological doses of zinc may be
effective in delaying the onset of symptomatic disease,
because zinc competes with copper for absorption in the
gastrointestinal tract.