Copper is an essential trace element that is vital to the health of all living things (humans,

plants, animals, and microorganisms). In humans, copper is essential to the proper

functioning of organs and metabolic processes. The human body has complex homeostatic
mechanisms which attempt to ensure a constant supply of available copper, while eliminating
excess copper whenever this occurs. However, like all essential elements and nutrients, too
much or too little nutritional ingestion of copper can result in a corresponding condition of
copper excess or deficiency in the body, each of which has its own unique set of adverse
health effects.
Daily dietary standards for copper have been set by various health agencies around the world.
Standards adopted by some nations recommend different copper intake levels for adults,
pregnant women, infants, and children, corresponding to the varying need for copper during
different stages of life.
Copper deficiency and toxicity can be either of genetic or non-genetic origin. The study of
copper's genetic diseases, which are the focus of intense international research activity, has
shed insight into how human bodies use copper, and why it is important as an essential
micronutrient. The studies have also resulted in successful treatments for genetic copper
excess conditions, enabling patients whose lives were once jeopardized to live long and
productive lives.
Researchers specializing in the fields of microbiology, toxicology, nutrition, and health risk
assessments are working together to define the precise copper levels that are required for
essentiality, while avoiding deficient or excess copper intakes. Results from these studies are
expected to be used to fine-tune governmental dietary recommendation programs which are
designed to help protect public health.

copper deficiency is a very rare hematological and neurological disorder.[1] The

neurodegenerative syndrome of copper deficiency has been recognized for some
time in ruminant animals, in which it is commonly known as "swayback"[2] Copper
is ubiquitous and daily requirement is low making acquired copper deficiency
very rare. Copper deficiency can manifest in parallel with vitamin B12 and other
nutritional deficiencies .[3] The most common cause of copper deficiency is a
remote gastrointestinal surgery, such as gastric bypass surgery, due to
malabsorption of copper, or zinc toxicity. On the other hand, Menkes disease is a
genetic disorder of copper deficiency involving a wide variety of symptoms that
is often fatal.[4] Copper is involved in normalized function of many enzymes, such
as cytochrome c oxidase, which is complex IV in mitochondrial electron transport
chain, ceruloplasmin, Cu/Zn superoxide dismutase, and in amine oxidases.[2]
These enzyme catalyze reactions for oxidative phosphorylation, iron
transportation, antioxidant and free radical scavenging and neutralization, and
neurotransmitter synthesis, respectively.[2] A regular diet contains a variable
amount of copper, but may provide 5 mg/day, of which only 20-50% is absorbed.
[3]
The diet of the elderly may contain a lower copper content than the
recommended daily intake.[3] Dietary copper can be found in whole grain cereals,
legumes, oysters, organ meats (particularly liver), cherries, dark chocolate,
fruits, leafy green vegetables, nuts, poultry, prunes, and soybeans products like

tofu.[5] The deficiency in copper can cause many hematological manifestations,

such as myelodysplasia, anemia, leukopenia (low white blood cell count) and
neutropenia (low count of neutrophils, a type of white blood cell that is often
called "the first line of defense" for the immune system). [3] Copper deficiency has
long been known for as a cause of myelodysplasia (when a blood profile has
indicators of possible future leukemia development), but it was not until recently
in 2001 that copper deficiency was associated with neurological manifestations.
Some neurological manifestations can be sensory ataxia (irregular coordination
due to proprioceptive loss), spasticity, muscle weakness, and more rarely visual
loss due to peripheral neuropathy (damage in the peripheral nerves),
myelopathy (disease of the spinal cord), and rarely optic neuropathy.

See also: Hematology

Anemia
o Insufficient red cell mass (anemia) can be the result of bleeding, blood
disorders like thalassemia, or nutritional deficiencies; and may require blood
transfusion. Several countries have blood banks to fill the demand for
transfusable blood. A person receiving a blood transfusion must have a blood
type compatible with that of the donor.
o Sickle-cell anemia

Disorders of cell proliferation

o Leukemia is a group of cancers of the blood-forming tissues and cells.
o Non-cancerous overproduction of red cells (polycythemia vera) or platelets
(essential thrombocytosis) may be premalignant.
o Myelodysplastic syndromes involve ineffective production of one or more cell
lines.

Disorders of coagulation
o Hemophilia is a genetic illness that causes dysfunction in one of the blood's
clotting mechanisms. This can allow otherwise inconsequential wounds to be
life-threatening, but more commonly results in hemarthrosis, or bleeding into
joint spaces, which can be crippling.
o Ineffective or insufficient platelets can also result in coagulopathy (bleeding
disorders).
o Hypercoagulable state (thrombophilia) results from defects in regulation of
platelet or clotting factor function, and can cause thrombosis.

Infectious disorders of blood

o Blood is an important vector of infection. HIV, the virus that causes AIDS, is
transmitted through contact with blood, semen or other body secretions of an
infected person. Hepatitis B and C are transmitted primarily through blood
contact. Owing to blood-borne infections, bloodstained objects are treated as a
biohazard.
o Bacterial infection of the blood is bacteremia or sepsis. Viral Infection is
viremia. Malaria and trypanosomiasis are blood-borne parasitic infections.

Blood

neurologists include headaches, radiculopathy, neuropathy, stroke, dementia, seizures and

epilepsy, Alzheimer's Disease, Attention deficit/hyperactivity disorder,[9][10] Parkinson's
Disease, Tourette's syndrome, multiple sclerosis, head trauma, sleep disorders, neuromuscular
diseases, and various infections and tumors of the nervous system. Neurologists are also
asked to evaluate unresponsive patients on life support in order to confirm brain death.
Treatment options vary depending on the neurological problem. They can include everything
from referring the patient to a physiotherapist, to prescribing medications, to recommending a
surgical procedure.
Menkes disease (MNK), also called Menkes syndrome, copper transport disease, steely
hair disease, kinky hair disease, or Menkes kinky hair syndrome,[1][2] is a disorder that
affects copper levels in the body,[3] leading to copper deficiency.[4][5] It is an x-linked recessive
disorder, and is therefore considerably more common in males: females require two defective
alleles to develop the disease.

Cause and genetics

Mutations in the ATP7A gene, located on chromosome Xq21.1,[9] are the cause of Menkes
syndrome.[10] This condition is inherited in an X-linked recessive pattern.[11] As the result of a
mutation in the ATP7A gene, copper is poorly distributed to cells in the body. Copper
accumulates in some tissues, such as the small intestine and kidneys, while the brain and
other tissues have unusually low levels. The decreased supply of copper can reduce the
activity of numerous copper-containing enzymes that are necessary for the structure and
function of bone, skin, hair, blood vessels and the nervous system such as lysyl oxidase.[12]

Diagnosis and treatment

Urine homovanillic acid/vanillylmandelic acid ratio has been proposed as a screening tool to
support earlier detection.[13] Early treatment with subcutaneous (under the skin) or
intravenous (in a vein) injections of copper supplements (in the form of acetate salts) may be
of some benefit.[14] Other treatment is symptomatic and supportive.
Ceruloplasmin is the major copper-carrying protein in the blood, and in addition
plays a role in iron metabolism. It was first described in 1948.[4] Another protein,
hephaestin, is noted for its homology to ceruloplasmin, and also participates in
iron and probably copper metabolism.

Deficiency
Lower-than-normal ceruloplasmin levels may indicate the following:

Wilson disease (a rare (UK incidence 1/100,000) copper storage disease) [9]

Menkes disease (Menkes kinky hair syndrome) (rare - UK incidence

1/100,000)

Overdose of Vitamin C

Copper deficiency

Aceruloplasminemia[10]

Excess
Greater-than-normal ceruloplasmin levels may indicate or be noticed in:

copper toxicity / zinc deficiency

pregnancy

oral contraceptive pill use[11]

lymphoma

acute and chronic inflammation (it is an acute-phase reactant)

rheumatoid arthritis

Angina[12]

Alzheimer's disease[13]

Schizophrenia[14]

Obsessive-compulsive disorder[15]

Wilson's disease
From Wikipedia, the free encyclopedia
(Redirected from Wilson disease)

Wilson's disease

A Kayser-Fleischer ring (the brown ring on the

edge of the iris) is common in Wilson's disease,
especially when neurological symptoms are
present

Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic

disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric
symptoms and liver disease. It is treated with medication that reduces copper absorption or
removes the excess copper from the body, but occasionally a liver transplant is required.[1]
The condition is due to mutations in the Wilson disease protein (ATP7B) gene. A single
abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms
(they are carriers). If a child inherits the gene from both parents, the child may develop
Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in
much older people have been described. Wilson's disease occurs in 1 to 4 per 100,000 people.
[1]
It is named after Samuel Alexander Kinnier Wilson (18781937), the British neurologist
who first described the condition in 1912.[2
Signs and symptoms

The main sites of copper accumulation are the liver and the brain, and consequently liver
disease and neuropsychiatric symptoms are the main features that lead to diagnosis.[1] People
with liver problems tend to come to medical attention earlier, generally as children or
teenagers, than those with neurological and psychiatric symptoms, who tend to be in their
twenties or older. Some are identified only because relatives have been diagnosed with
Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms
of the condition but have not received a diagnosis.[3]
Liver disease
Liver disease may present itself as tiredness, increased bleeding tendency or confusion (due
to hepatic encephalopathy) and portal hypertension. The latter, a condition in which the
pressure in the portal vein is markedly increased, leads to esophageal varices, blood vessels in
the esophagus that may bleed in a life-threatening fashion, as well as enlargement of the
spleen (splenomegaly) and accumulation of fluid in the abdominal cavity (ascites). On
examination, signs of chronic liver disease such as spider angiomata (small distended blood
vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis
of the liver in most by the time they develop symptoms. While most people with cirrhosis
have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very
low in Wilson's disease.[1]
About 5% of all people are diagnosed only when they develop fulminant acute liver failure,
often in the context of a hemolytic anemia (anemia due to the destruction of red blood cells).
This leads to abnormalities in protein production (identified by deranged coagulation) and
metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste
products such as ammonia in the bloodstream. When these irritate the brain, the person
develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening
swelling of the brain).[1]
Neuropsychiatric symptoms
About half the people with Wilson's disease have neurological or psychiatric symptoms. Most
initially have mild cognitive deterioration and clumsiness, as well as changes in behavior.
Specific neurological symptoms usually then follow, often in the form of parkinsonism
(cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most
common parkinsonian features[4]) with or without a typical hand tremor, masked facial
expressions, slurred speech, ataxia (lack of coordination) or dystonia (twisting and repetitive
movements of part of the body). Seizures and migraine appear to be more common in
Wilson's disease.[1] A characteristic tremor described as "wing-beating tremor" is encountered
in many people with Wilson's; this is absent at rest but can be provoked by extending the
arms.[5]
Cognition can also be affected in Wilson's disease. This comes in two, not mutually
exclusive, categories: frontal lobe disorder (may present as impulsivity, impaired judgement,
promiscuity, apathy and executive dysfunction with poor planning and decision making) and
subcortical dementia (may present as slow thinking, memory loss and executive dysfunction,
without signs of aphasia, apraxia or agnosia). It is suggested that these cognitive
involvements are related and closely linked to psychiatric manifestations of the disease.[4]

Psychiatric problems due to Wilson's disease may include behavioral changes, depression,
anxiety and psychosis.[1] Psychiatric symptoms are commonly seen in conjunction with
neurological symptoms and are rarely manifested on their own. These symptoms are often
poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of
Wilson's disease is rarely made when only psychiatric symptoms are present.[4]
Other organ systems
Medical conditions have been linked with copper accumulation in Wilson's disease:

Eyes: KayserFleischer rings (KF rings), a pathognomonic sign, may be

visible in the cornea of the eyes, either directly or on slit lamp examination
as deposits of copper in a ring around the cornea. They are due to copper
deposition in Descemet's membrane. They do not occur in all people with
Wilson's disease. Wilson's disease is also associated with sunflower
cataracts exhibited by brown or green pigmentation of the anterior and
posterior lens capsule.[6] Neither cause significant visual loss. [1] KF rings
occur in approximately 66% of diagnosed cases (more often in those with
neurological symptoms rather than with liver problems). [3]

Kidneys: renal tubular acidosis, a disorder of bicarbonate handling by the

proximal tubules leads to nephrocalcinosis (calcium accumulation in the
kidneys), a weakening of bones (due to calcium and phosphate loss), and
occasionally aminoaciduria (loss of essential amino acids needed for
protein synthesis).[1]

Heart: cardiomyopathy (weakness of the heart muscle) is a rare but

recognized problem in Wilson's disease; it may lead to heart failure (fluid
accumulation due to decreased pump function) and cardiac arrhythmias
(episodes of irregular and/or abnormally fast or slow heart beat). [1]

Hormones: hypoparathyroidism (failure of the parathyroid glands leading

to low calcium levels), infertility, and habitual abortion.[1]

Genetics

Wilson's disease has an autosomal recessive pattern of inheritance.

Main article: ATP7B

The Wilson's disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is
expressed primarily in the liver, kidney, and placenta. The gene codes for a P-type (cation
transport enzyme) ATPase that transports copper into bile and incorporates it into
ceruloplasmin.[1] Mutations can be detected in 90%. Most (60%) are homozygous for ATP7B
mutations (two abnormal copies), and 30% have only one abnormal copy. Ten percent have
no detectable mutation.[3]
Although 300 mutations of ATP7B have been described, in most populations the cases of
Wilson's disease are due to a small number of mutations specific for that population. For
instance, in Western populations the H1069Q mutation (replacement of a histidine by a
glutamine at position 1069 in the protein) is present in 3763% of cases, while in China this
mutation is very uncommon and R778L (arginine to leucine at 778) is found more often.
Relatively little is known about the relative impact of various mutations, although the
H1069Q mutation seems to predict later onset and predominantly neurological problems,
according to some studies.[1][7]
A normal variation in the PRNP gene can modify the course of the disease by delaying the
age of onset and affecting the type of symptoms that develop. This gene produces prion
protein, which is active in the brain and other tissues and also appears to be involved in
transporting copper.[8] A role for the ApoE gene was initially suspected but could not be
confirmed.[7]
The condition is inherited in an autosomal recessive pattern. In order to inherit it, both of the
parents of an individual must carry an affected gene. Most have no family history of the
condition.[7] People with only one abnormal gene are called carriers (heterozygotes) and may
have mild, but medically insignificant, abnormalities of copper metabolism.[9]
Wilson's disease is the most common of a group of hereditary diseases that cause copper
overload in the liver. All can cause cirrhosis at a young age. The other members of the group
are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic
copper toxicosis. These are not related to ATP7B mutations: for example, ICC has been
linked to mutations in the KRT8 and the KRT18 gene.[7]
Pathophysiology

Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin,

green = ATP7B carrying copper.

Copper is needed by the body for a number of functions, predominantly as a cofactor for a
number of enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine -hydroxylase,
superoxide dismutase and tyrosinase.[7]
Copper enters the body through the digestive tract. A transporter protein on the cells of the
small bowel, copper membrane transporter 1 (CMT1), carries copper inside the cells, where
some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the
trans-Golgi network. Here, in response to rising concentrations of copper, an enzyme called
ATP7A releases copper into the portal vein to the liver. Liver cells also carry the CMT1
protein, and metallothionein and ATOX1 bind it inside the cell, but here it is ATP7B that links
copper to ceruloplasmin and releases it into the bloodstream, as well as removing excess
copper by secreting it into bile. Both functions of ATP7B are impaired in Wilson's disease.
Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks
copper (termed apoceruloplasmin) and is rapidly degraded in the bloodstream.[7]
When the amount of copper in the liver overwhelms the proteins that normally bind it, it
causes oxidative damage through a process known as Fenton chemistry; this damage
eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue) and
cirrhosis. The liver also releases copper into the bloodstream that is not bound to
ceruloplasmin. This free copper precipitates throughout the body but particularly in the
kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia,
particularly in the putamen and globus pallidus (together called the lenticular nucleus); these
areas normally participate in the coordination of movement as well as playing a significant
role in neurocognitive processes such as the processing of stimuli and mood regulation.
Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms
seen in Wilson's disease.[7]

It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest
that high levels of free (non-ceruloplasmin bound) copper have a direct effect on either
oxidation of hemoglobin, inhibition of energy-supplying enzymes in the red blood cell, or
direct damage to the cell membrane.[10]
Diagnosis

Location of the basal ganglia, the part of the brain affected by Wilson's disease

Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or
when a close relative has been found to have Wilson's. Most have slightly abnormal liver
function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin
level. If the liver damage is significant, albumin may be decreased due to an inability of
damaged liver cells to produce this protein; likewise, the prothrombin time (a test of
coagulation) may be prolonged as the liver is unable to produce proteins known as clotting
factors.[1] Alkaline phosphatase levels are relatively low in those with Wilson's-related acute
liver failure.[11] If there are neurological symptoms, magnetic resonance imaging (MRI) of the
brain is usually performed; this shows hyperintensities in the part of the brain called the basal
ganglia in the T2 setting.[9] MRI may also demonstrate the characteristic "face of the giant
panda" pattern.[12]
There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in
the blood, as well of the amount of copper excreted in urine during a 24-hour period, are
together used to form an impression of the amount of copper in the body. The gold standard
or most ideal test is a liver biopsy.[1]
Ceruloplasmin

Ceruloplasmin

Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 8095% of cases.[1] It can,
however, be present at normal levels in people with ongoing inflammation as it is an acute
phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia,
which are related to, but much rarer than Wilson's disease.[1][9]
The combination of neurological symptoms, KayserFleisher rings and a low ceruloplasmin
level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however,
further tests are needed.[9]
Serum and urine copper
Serum copper is paradoxically low but urine copper is elevated in Wilson's disease. Urine is
collected for 24 hours in a bottle with a copper-free liner. Levels above 100 g/24h
(1.6 mol/24h) confirm Wilson's disease, and levels above 40 g/24h (0.6 mol/24h) are
strongly indicative.[1] High urine copper levels are not unique to Wilson's disease; they are
sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the
flow of bile from the liver to the small bowel).[9]
In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is
administered, and urine collected for 24 hours. If this contains more than 1600 g (25 mol),
it is a reliable indicator of Wilson's disease. This test has not been validated in adults.[9]
Liver biopsy
Once other investigations have indicated Wilson's disease, the ideal test is the removal of a
small amount of liver tissue through a liver biopsy. This is assessed microscopically for the
degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to
measure the severity of the copper accumulation. A level of 250 g of copper per gram of
dried liver tissue confirms Wilson's disease. Occasionally, lower levels of copper are found;
in that case, the combination of the biopsy findings with all other tests could still lead to a
formal diagnosis of Wilson's.[1]
In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty
material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more
advanced disease, the changes observed are quite similar to those seen in autoimmune
hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar
tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure,
degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on
a background of cirrhotic changes. Histochemical methods for detecting copper are
inconsistent and unreliable, and taken alone are regarded as insufficient to establish a
diagnosis.[9]
Genetic testing
Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in
the liver, may be performed. Once a mutation is confirmed, it is possible to screen family
members for the disease as part of clinical genetics family counseling.[1]
Treatment

Dietary
In general, a diet low in copper-containing foods is recommended with the avoidance of
mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.[1]
Medication
Medical treatments are available for Wilson's disease. Some increase the removal of copper
from the body, while others prevent the absorption of copper from the diet.
Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to
excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can
be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems:
about 20% experience a side effect or complication of penicillamine treatment, such as druginduced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading
to muscle weakness). In those who presented with neurological symptoms, almost half
experience a paradoxical worsening in their symptoms. While this phenomenon is observed
in other treatments for Wilson's, it is usually taken as an indication for discontinuing
penicillamine and commencing second-line treatment.[1][9] Those intolerant to penicillamine
may instead be commenced on trientine hydrochloride, which also has chelating properties.
Some recommend trientine as first-line treatment, but experience with penicillamine is more
extensive.[9] A further agent, under clinical investigation, with known activity in Wilson's
disease is tetrathiomolybdate. This is regarded as experimental,[9] though some studies have
shown a beneficial effect.[1]
Once all results have returned to normal, zinc (usually in the form of a zinc acetate
prescription called Galzin) may be used instead of chelators to maintain stable copper levels
in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and
prevents their absorption and transport to the liver. Zinc therapy is continued unless
symptoms recur or if the urinary excretion of copper increases.[9]
In rare cases where none of the oral treatments are effective, especially in severe neurological
disease, dimercaprol (British anti-Lewisite) is occasionally necessary. This treatment is
injected intramuscularly (into a muscle) every few weeks and has unpleasant side effects such
as pain.[13]
People who are asymptomatic (for instance, those diagnosed through family screening or
only as a result of abnormal test results) are generally treated, as the copper accumulation
may cause long-term damage in the future. It is unclear whether these people are best treated
with penicillamine or zinc acetate.[9]
Physical therapy
Physiotherapy is beneficial for patients with the neurologic form of the disease. The copper
chelating treatment may take up to six months to start working, and physical therapy can
assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of
contractures that can result from dystonia.[14]

Transplantation
Liver transplantation is an effective cure for Wilson's disease but is used only in particular
scenarios because of the risks and complications associated with the procedure. It is used
mainly in people with fulminant liver failure who fail to respond to medical treatment or in
those with advanced chronic liver disease. Liver transplantation is avoided in severe
neuropsychiatric illness, in which its benefit has not been demonstrated.[1][9]
Prognosis

Left untreated, Wilson's disease tends to become progressively worse and is eventually fatal.
With early detection and treatment, most of those affected can live relatively normal lives.
Liver and neurologic damage that occurs prior to treatment may improve, but it is often
permanent.[citation needed]
History

The disease bears the name of the British physician Samuel Alexander Kinnier Wilson
(18781937), a neurologist who described the condition, including the pathological changes
in the brain and liver, in 1912.[2] Wilson's work had been predated by, and drew on, reports
from German neurologist Carl Westphal (in 1883), who termed it "pseudosclerosis"; by the
British neurologist William Gowers (in 1888); and by Adolph Strmpell (in 1898), who noted
hepatic cirrhosis.[15] Neuropathologist John Nathaniel Cumings made the link with copper
accumulation in both the liver and the brain in 1948.[16] The occurrence of hemolysis was
noted in 1967.[17]
Cumings, and simultaneously the New Zealand neurologist Derek Denny-Brown, working in
the United States, first reported effective treatment with metal chelator British anti-Lewisite
in 1951.[18][19] This treatment had to be injected but was one of the first therapies available in
the field of neurology, a field that classically was able to observe and diagnose but had few
treatments to offer.[15][20] The first effective oral chelation agent, penicillamine, was discovered
in 1956 by British neurologist John Walshe.[21] In 1982, Walshe also introduced trientine,[22]
and was the first to develop tetrathiomolybdate for clinical use.[23] Zinc acetate therapy
initially made its appearance in the Netherlands, where physicians Schouwink and
Hoogenraad used it in 1961 and in the 1970s, respectively, but it was further developed later
by Brewer and colleagues at the University of Michigan.[13][24]
The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the
1980s and 1990s by several research groups.[25][26]
copper is absorbed in the stomach and small intestine, although there appear to be differences
among species with respect to the site of maximal absorption.[20] Copper is absorbed from the
stomach and duodenum in rats[21] and from the lower small intestine in hamsters.[22] The site
of maximal copper absorption is not known for humans, but is assumed to be the stomach and
upper intestine because of the rapid appearance of Cu64 in the plasma after oral
administration.[23]
Absorption of copper ranges from 1597%, depending on copper content, form of the copper,
and composition of the diet.[24][25][26][27][28]

Various factors influence copper absorption. For example, copper absorption is enhanced by
ingestion of animal protein, citrate, and phosphate. Copper salts, including copper gluconate,
copper acetate, or copper sulfate, are more easily absorbed than copper oxides[disambiguation needed].
[29][30]
Elevated levels of dietary zinc, as well as cadmium, high intakes of phytate and simple
sugars (fructose, sucrose) inhibit dietary absorption of copper.[31][32][33][34][35][36] Furthermore,
low levels of dietary copper inhibit iron absorption.
Some forms of copper are not soluble in stomach acids and cannot be absorbed from the
stomach or small intestine. Also, some foods may contain indigestible fiber that binds with
copper. High intakes of zinc can significantly decrease copper absorption. Extreme intakes of
Vitamin C or iron can also affect copper absorption, reminding us of the fact that
micronutrients need to be consumed as a balanced mixture. This is one reason why extreme
intakes of any one single micronutrient are not advised.[37] Individuals with chronic digestive
problems may be unable to absorb sufficient amounts of copper, even though the foods they
eat are copper-rich.
Several copper transporters have been identified that can move copper across cell
membranes.[38][39] Other intestinal copper transporters may exist. Intestinal copper uptake may
be catalyzed by Ctr1. Ctr1 is expressed in all cell types so far investigated, including
enterocytes, and it catalyzes the transport of Cu+1 across the cell membrane.[40]
Excess copper (as well as other heavy metal ions like zinc or cadmium) may be bound by
metallothionein and sequestered within intracellular vesicles of enterocytes (i.e., predominant
cells in the small intestinal mucosa).
Distribution
Copper released from intestinal cells moves to the serosal (i.e., thin membrane lining)
capillaries where it binds to albumin, glutathione, and amino acids in the portal blood.[41][42]
There is also evidence for a small protein, transcuprein, with a specific role in plasma copper
transport[43] Several or all of these copper-binding molecules may participate in serum copper
transport. Copper from portal circulation is primarily taken up by the liver. Once in the liver,
copper is either incorporated into copper-requiring proteins, which are subsequently secreted
into the blood. Most of the copper (70 95%) excreted by the liver is incorporated into
ceruloplasmin, the main copper carrier in blood. Copper is transported to extra-hepatic tissues
by ceruloplasmin,[44] albumin and amino acids, or excreted into the bile.[45] By regulating
copper release, the liver exerts homeostatic control over extrahepatic copper.[13]
Excretion
Bile is the major pathway for the excretion of copper and is vitally important in the control of
liver copper levels.[46][47][48] Most fecal copper results from biliary excretion; the remainder is
derived from unabsorbed copper and copper from desquamated mucosal cells.
postulated spectrum of copper metabolism [49]
Dose Approximate
range daily intakes

Health outcomes

Death
Gross dysfunction and disturbance of metabolism of
other nutrients; hepatic

"detoxification" and homeostasis overwhelmed

Toxic

>5.0 mg/kg
body weight
100 g/kg
body weight

Gastrointestinal metallothionein induced (possible

differing effects of acute and chronic

exposure)
Plateau of absorption maintained; homeostatic
mechanisms regulate absorption of copper

Hepatic uptake, sequestration and excretion effect

Adequat 34 g/kg body homeostasis; glutathione-dependent uptake of copper;
e
weight
binding to metallothionein; and lysosomal excretion of
copper
11 g/kg body
Biliary excretion and gastrointestinal uptake normal
weight
9 g/kg body
weight
Deficien 8.5 g/kg
t
body weight
5.2 g/kg
body weight

2 g/kg body
weight

Hepatic deposit(s) reduced; conservation of endogenous

copper; gastrointestinal

absorption increased
Negative copper balance
Functional defects, such as lysyl oxidase and superoxide
dismutase activities reduced; impaired substrate
metabolism
Peripheral pools disrupted; gross dysfunction and
disturbance of metabolism of other

nutrients; death

Daily dietary copper requirements

Various national and international organizations concerned with nutrition and health have
standards for copper intake at levels judged to be adequate for maintaining good health.
These standards, or dietary reference values, are periodically changed and updated as new
scientific data become available. The standards sometimes differ among regions and
organizations.
Adults
The World Health Organization recommends a minimal acceptable intake of approximately
1.3 mg/day.[50] These values are considered to be adequate and safe for most of the general
population. In North America, the recommended intake of copper for healthy adult men and

women is 900 micrograms/day (0.9 mg/day).[51][52][53] Health benefits above the recommended
adequate intake of 0.9 - 1.3 mg/day have not been established.
In North America, a maximum tolerable intake has been established at 10 mg/day. This is the
highest level of copper intake that is not likely to pose a health risk to most adults in the
general population. However, this daily intake level is not recommended by any authority.
Adolescents, children, and infants
The World Health Organization has not developed minimum daily intakes for these age
groups. In North America, safe and acceptable daily intakes have been estimated from adult
data and are as follows: 340 micrograms/day (0.34 mg/day) for children of 13 years; 440
micrograms/day (0.44 mg/day) for 48 years; 700 micrograms/day (0.7 mg/day) for 913
years; and 890 micrograms/day (0.89 mg/day) for 1418 years.[51][52][54]
In North America, tolerable intakes for these age groups (i.e., intakes not likely to pose a
health risk for most children in the general population, but for which no additional health
benefits are known) are: 1 mg/day for children of 13 years; 3 mg/day for 48 years;
5 mg/day for 913 years; and 8 mg/day for 1418 years.
Full-term and premature infants are more sensitive to copper deficiency than adults. Since the
fetus accumulates copper during the last 3 months of pregnancy, infants that are born
prematurely have not had sufficient time to store adequate reserves of copper in their livers
and therefore require more copper at birth than full-term infants.
For full-term infants, the North American recommended safe and adequate intake is
approximately 0.2 mg/day. For premature babies, it is considerably higher: 1 mg/day. The
World Health Organization has recommended similar minimum adequate intakes and advises
that premature infants be given formula supplemented with extra copper to prevent the
development of copper deficiency.[55]
Pregnant women and mothers who breastfeed
Nature has devised a way for the fetus to get copper from the mother via the placenta and for
infants to get copper via breast milk. For these reasons, pregnancy and nursing increase the
body's need for copper. The recommended oral intake in pregnant and nursing women is
slightly higher than for non-pregnant, non-nursing healthy women (approximately 1 mg/day
for pregnant women and 1.3 mg/day for nursing mothers aged 1450 years).[55]
The best source of copper and other essential micronutrients during the first year of life is
human milk. If a full-term infant is not nursed, fortified baby formula is highly
recommended. Cow's milk, however, contains very low amounts of bioavailable copper and
should be supplemented with copper during the first year of life.
Dietary sources

Foods rich in copper

Copper is an essential trace mineral that cannot be formed by the human body. It must be
ingested from dietary sources.
Foods contribute virtually all of the copper consumed by humans.[56][57][58] The best dietary
sources include seafood (especially shellfish), organ meats (e.g., liver), whole grains, legumes
(e.g., beans and lentils) and chocolate. Nuts, including peanuts and pecans, are especially rich
in copper, as are grains such as wheat and rye, and several fruits including lemons and raisins.
Other food sources that contain copper include cereals, potatoes, peas, red meat, mushrooms,
some dark green leafy vegetables (such as kale), and fruits (coconuts, papaya and apples).
Tea, rice and chicken are relatively low in copper, but can provide a reasonable amount of
copper when they are consumed in significant amounts.
Eating a balanced diet with a range of foods from different food groups is the best way to
avoid copper deficiency. In both developed and developing countries, adults, young children,
and adolescents who consume diets of grain, millet, tuber, or rice along with legumes (beans)
or small amounts of fish or meat, some fruits and vegetables, and some vegetable oil are
likely to obtain adequate copper if their total food consumption is adequate in calories. In
developed countries where consumption of red meat is high, copper intake is also likely to be
adequate.
As a natural element in the earth's crust, copper exists in most of the world's surface water
and groundwater, although the actual concentration of copper in natural waters varies
geographically. Drinking water can comprise 20-25% of dietary copper.[59]
In many regions of the world, copper tubing that conveys drinking water can be a source of
dietary copper. Copper tube can leach a small amount of copper, particularly in its first year
or two of service. Afterwards, a protective surface usually forms on the inside of copper tubes
that retards leaching.
Supplementation
Copper supplements can prevent copper deficiency, but supplements should be taken only
under a doctor's supervision. Different forms of copper supplementation have different
absorption rates. For example, the absorption of copper from cupric oxide supplements is
lower than that from copper gluconate, sulfate, or carbonate.

Supplementation is generally not recommended for healthy adults who consume a wellbalanced diet which includes a wide range of foods. However, supplementation under the
care of a physician may be necessary for premature infants or those with low birth weights,
infants fed unfortified formula or cow's milk during the first year of life, and malnourished
young children. Physicians may consider copper supplementation for 1) illnesses that reduce
digestion (e.g., children with frequent diarrhea or infections; alcoholics), 2) insufficient food
consumption (e.g., the elderly, the infirm, those with eating disorders or on diets), 3) patients
taking medications that block the body's use of copper, 4) anemia patients who are treated
with iron supplements, 5) anyone taking zinc supplements, and 6) those suffering from
osteoporosis.
Many popular vitamin supplements include copper as small inorganic molecules such as
cupric oxide. These supplements can result in excess free copper in the brain as the copper
can cross the blood-brain barrier directly. Normally, organic copper in food is first processed
by the liver which keeps free copper levels under control.
Copper deficiency and excess health conditions (non-genetic)
Main article: Copper deficiency

If insufficient quantities of copper are ingested, copper reserves in the liver will become
depleted and a copper deficiency leading to disease or tissue injury (and in extreme cases,
death). Toxicity from copper deficiency can be treated with a balanced diet or
supplementation under the supervision of a doctor. On the contrary, like all substances, excess
copper intake at levels far above World Health Organization limits can become toxic.[60]
Acute copper toxicity is generally associated with accidental ingestion. These symptoms
abate when the high copper food source is no longer ingested.
In 1996, the International Program on Chemical Safety, a World Health Organizationassociated agency, stated "there is greater risk of health effects from deficiency of copper
intake than from excess copper intake." This conclusion was confirmed in recent multi-route
exposure surveys.[61][62]
The health conditions of non-genetic copper deficiency and copper excess are described
below.
Copper deficiency
A number of nutrition surveys have indicated that the diets of approximately 25% of
adolescents, adults, and people over 65, do not meet the recommended daily nutrient intake
for copper.[10] These studies also suggest that long-term acquired copper deficiency is underdiagnosed and is much more common than suspected.
Acquired copper deficiency has recently been implicated in adult-onset progressive
myeloneuropathy[63] and in the development of severe blood disorders including
myelodysplastic syndrome.[11][64][65] Fortunately, copper deficiency can be confirmed by very
low serum metal and ceruloplasmin concentrations in the blood.

Other conditions previously linked to copper deficiency include osteoporosis, osteoarthritis,

rheumatoid arthritis, cardiovascular disease, colon cancer, and chronic conditions involving
bone, connective tissue, heart, and blood vessels.[7][66][67][68][69]
Copper deficiency alters the role of other cellular constituents involved in antioxidant
activities, such as iron, selenium, and glutathione, and therefore plays an important role in
diseases in which oxidant stress is elevated.[70][71][72]
In both humans and animals, the major target organs for copper deficiency are the blood and
hematopoietic system, the cardiovascular system, connective tissue and bone, the nervous
system, and the immune system.[3][9][67]
A marginal (i.e., 'mild') copper deficiency, believed to be more widespread than previously
thought, can impair human health in subtle ways.[59] Those affected suffer from lowered
resistance to infection, general fatigue, impaired neurological function, and elevated risk for
coronary heart disease and osteoporosis.
Populations susceptible to copper deficiency include those with genetic defects for Menkes
disease, low-birth-weight infants, infants fed cow's milk instead of breast milk or fortified
formula, pregnant and lactating mothers, patients receiving total parenteral nutrition,
individuals with "malabsorption syndrome" (impaired dietary absorption), diabetics,
individuals with chronic diseases that result in low food intake, such as alcoholics, and
persons with eating disorders. The elderly and athletes may also be at higher risk for copper
deficiency due to special needs that increase the daily requirements.[36] Vegetarians may have
decreased copper intake due to the consumption of plant foods in which copper
bioavailability is low.[33][73][74] Fetuses and infants of severely copper deficient women have
increased risk of low birth weights, muscle weaknesses, and neurological problems. Copper
deficiencies in these populations may result in anemia, bone abnormalities, impaired growth,
weight gain, frequent infections (colds, flu, pneumonia), poor motor coordination, and low
energy.
Copper excess
Main article: Copper toxicity

Copper excess is a subject of much current research. Distinctions have emerged from studies
that copper excess factors are different in normal populations versus those with increased
susceptibility to adverse effects and those with rare genetic diseases.[9][59] This has led to
statements from health organizations that could be confusing to the uninformed. For example,
according to a U.S. Institute of Medicine report,[75] the intake levels of copper for a significant
percentage of the population are lower than recommended levels. On the other hand, the U.S.
National Research Council[76] concluded in its report Copper in Drinking Water that there is
concern for copper toxicity in susceptible populations and recommended that additional
research be conducted to identify and characterize copper-sensitive populations.
Excess copper intake causes stomach upset, nausea, and diarrhea and can lead to tissue injury
and disease.

The oxidation potential of copper may be responsible for some of its toxicity in excess
ingestion cases. At high concentrations copper is known to produce oxidative damage to
biological systems, including peroxidation of lipids or other macromolecules.[77]
While the cause and progression of Alzheimer's disease are not well understood,[78] research
indicates that, among several other key observations, iron,[79][80] aluminum,[81] and copper[82][83]
accumulate in the brains of Alzheimer's patients. However, it is not yet known whether this
accumulation is a cause or a consequence of the disease.
Research has been ongoing over the past two decades to determine whether copper is a
causative or a preventive agent of Alzheimer's disease, and whether copper accumulates due
to a metal homeostasis disturbance that develops in individuals with Alzheimer's disease.[84]
For example, as a possible causative agent or an expression of a metal homeostasis
disturbance, studies indicate that copper may play a role in increasing the growth of protein
clumps in Alzheimer's disease brains,[85] possibly by damaging a molecule that removes the
toxic buildup of amyloid beta (A) in the brain.[86] On the other hand, studies also
demonstrate potential beneficial roles of copper in treating rather than causing Alzheimer's
disease.[87] For example, copper has been shown to 1) promote the non-amyloidogenic
processing of amyloid beta precursor protein (APP), thereby lowering amyloid beta (A)
production in cell culture systems[88] 2) increase lifetime and decrease soluble amyloid
production in APP transgenic mice, and 3) lower A levels in cerebral spinal fluid in
Alzheimer's disease patients.[89]
Furthermore, long-term copper treatment (oral intake of 8 mg copper (Cu-(II)-orotatedihydrate)) was excluded as a risk factor for Alzheimer's disease in a noted clinical trial on
humans[90] and a potentially beneficial role of copper in Alzheimer's disease has been
demonstrated on cerebral spinal fluid levels of A42, a toxic peptide and biomarker of the
disease.[91] More research is needed to understand metal homeostasis disturbances in
Alzheimer's disease patients and how to address these disturbances therapeutically. Since this
experiment used Cu-(II)-orotate-dihydrate, it does not relate to the effects of cupric oxide in
supplements.
Copper toxicity from excess exposures
In humans, the liver is the primary organ of copper-induced toxicity. Other target organs
include bone and the central nervous and immune systems.[9] Excess copper intake also
induces toxicity indirectly by interacting with other nutrients. For example, excess copper
intake produces anemia by interfering with iron transport and/or metabolism.[3][9]
The identification of genetic disorders of copper metabolism leading to severe copper toxicity
(i.e., Wilson disease) has spurred research into the molecular genetics and biology of copper
homeostasis (for further information, refer to the following section on copper genetic
diseases). Much attention has focused on the potential consequences of copper toxicity in
normal and potentially susceptible populations. Potentially susceptible subpopulations
include hemodialysis patients and individuals with chronic liver disease. Recently, concern
was expressed about the potential sensitivity to liver disease of individuals who are
heterozygote carriers of Wilson disease genetic defects (i.e., those having one normal and one
mutated Wilson copper ATPase gene) but who do not have the disease (which requires defects

in both relevant genes).[92] However, to date, no data are available that either support or refute
this hypothesis.
Acute exposures
In case reports of humans intentionally or accidentally ingesting high concentrations of
copper salts (doses usually not known but reported to be 2070 grams of copper), a
progression of symptoms was observed including abdominal pain, headache, nausea,
dizziness, vomiting and diarrhea, tachycardia, respiratory difficulty, hemolytic anemia,
hematuria, massive gastrointestinal bleeding, liver and kidney failure, and death.
Episodes of acute gastrointestinal upset following single or repeated ingestion of drinking
water containing elevated levels of copper (generally above 36 mg/L) are characterized by
nausea, vomiting, and stomach irritation. These symptoms resolve when copper in the
drinking water source is reduced.
Three experimental studies were conducted that demonstrate a threshold for acute
gastrointestinal upset of approximately 45 mg/L in healthy adults, although it is not clear
from these findings whether symptoms are due to acutely irritant effects of copper and/or to
metallic, bitter, salty taste.[93][94][95][96] In an experimental study with healthy adults, the average
taste threshold for copper sulfate and chloride in tap water, deionized water, or mineral water
was 2.53.5 mg/L.[97] This is just below the experimental threshold for acute gastrointestinal
upset.
Chronic exposures
The long-term toxicity of copper has not been well studied in humans, but it is infrequent in
normal populations that do not have a hereditary defect in copper homeostasis.[98]
There is little evidence to indicate that chronic human exposure to copper results in systemic
effects other than liver injury.[99] Chronic copper poisoning leading to liver failure was
reported in a young adult male with no known genetic susceptibility who consumed 30
60 mg/d of copper as a mineral supplement for 3 years.[100] Individuals residing in U.S.
households supplied with tap water containing >3 mg/L of copper exhibited no adverse health
effects.[101]
No effects of copper supplementation on serum liver enzymes, biomarkers of oxidative stress,
and other biochemical endpoints have been observed in healthy young human volunteers
given daily doses of 6 to 10 mg/d of copper for up to 12 weeks.[102][103][104][105] Infants aged 3
12 months who consumed water containing 2 mg Cu/L for 9 months did not differ from a
concurrent control group in gastrointestinal tract (GIT) symptoms, growth rate, morbidity,
serum liver enzyme and bilirubin levels, and other biochemical endpoints.[106]) Serum
ceruloplasmin was transiently elevated in the exposed infant group at 9 months and similar to
controls at 12 months, suggesting homeostatic adaptation and/or maturation of the
homeostatic response.[11]
Dermal exposure has not been associated with systemic toxicity but anecdotal reports of
allergic responses may be a sensitization to nickel and cross-reaction with copper or a skin
irritation from copper.[9] Workers exposed to high air levels of copper (resulting in an

estimated intake of 200 mg Cu/d) developed signs suggesting copper toxicity (e.g., elevated
serum copper levels, hepatomegaly). However, other co-occurring exposures to pesticidal
agents or in mining and smelting may contribute to these effects.[9] Effects of copper
inhalation are being thoroughly investigated by an industry-sponsored program on workplace
air and worker safety. This multi-year research effort is expected to be finalized in 2011.
Measurements of elevated copper status
Although a number of indicators are useful in diagnosing copper deficiency, there are no
reliable biomarkers of copper excess resulting from dietary intake. The most reliable indicator
of excess copper status is liver copper concentration. However, measurement of this endpoint
in humans is intrusive and not generally conducted except in cases of suspected copper
poisoning. Increased serum copper or ceruolplasmin levels are not reliably associated with
copper toxicity as elevations in concentrations can be induced by inflammation, infection,
disease, malignancies, pregnancy, and other biological stressors. Levels of copper-containing
enzymes, such as cytochrome c oxidase, superoxide dismutase, and diaminase oxidase, vary
not only in response to copper state but also in response to a variety of other physiological
and biochemical factors and therefore are inconsistent markers of excess copper status.[107]
A new candidate biomarker for copper excess as well as deficiency has emerged in recent
years. This potential marker is a chaperone protein, which delivers copper to the antioxidant
protein SOD1 (copper, zinc superoxide dismutase). It is called "copper chaperone for SOD1"
(CCS), and excellent animal data supports its use as a marker in accessible cells (e.g.,
erythrocytes) for copper deficiency as well as excess. CCS is currently being tested as a
biomarker in humans.
Hereditary copper metabolic diseases

Several rare genetic diseases (Wilson disease, Menkes disease, idiopathic copper toxicosis,
Indian childhood cirrhosis) are associated with the improper utilization of copper in the body.
[108]
All of these diseases involve mutations of genes containing the genetic codes for the
production of specific proteins involved in the absorption and distribution of copper. When
these proteins are dysfunctional, copper either builds up in the liver or the body fails to
absorb copper.
These diseases are inherited and cannot be acquired. Adjusting copper levels in the diet or
drinking water will not cure these conditions (although therapies are available to manage
symptoms of genetic copper excess disease).
The study of genetic copper metabolism diseases and their associated proteins are enabling
scientists to understand how human bodies use copper and why it is important as an essential
micronutrient.
The diseases arise from defects in two similar copper pumps, the Menkes and the Wilson CuATPases.[109] The Menkes ATPase is expressed in tissues like skin-building fibroblasts,
kidneys, placenta, brain, gut and vascular system, while the Wilson ATPase is expressed
mainly in the liver, but also in mammary glands and possibly in other specialized tissues.[9]
This knowledge is leading scientists towards possible cures for genetic copper diseases.[60]

Menkes disease
Menkes disease, a genetic condition of copper deficiency, was first described by John
Menkes in 1962. It is a rare X-linked disorder that affects approximately 1/200,000 live
births, primarily boys.[7] Livers of Menkes disease patients cannot absorb essential copper
needed for patients to survive. Death usually occurs in early childhood: most affected
individuals die before the age of 10 years, although several patients have survived into their
teens and early 20s.[110]
The protein produced by the Menkes gene is responsible for transporting copper across the
gastrointestinal tract (GIT) mucosa and the bloodbrain barrier.[11][110] Mutational defects in
the gene encoding the copper ATPase cause copper to remain trapped in the lining of the
small intestine. Hence, copper cannot be pumped out of the intestinal cells and into the blood
for transport to the liver and consequently to rest of the body.[110][111] The disease therefore
resembles a severe nutritional copper deficiency despite adequate ingestion of copper.
Symptoms of the disease include coarse, brittle, depigmented hair and other neonatal
problems, including the inability to control body temperature, mental retardation, skeletal
defects, and abnormal connective tissue growth.
Menkes patients exhibit severe neurological abnormalities, apparently due to the lack of
several copper-dependent enzymes required for brain development,[59][112] including reduced
cytochrome c oxidase activity.[110] The brittle, kinky hypopigmented hair of steely appearance
is due to a deficiency in an unidentified cuproenzyme. Reduced lysyl oxidase activity results
in defective collagen and elastin polymerization and corresponding connective-tissue
abnormalities including aortic aneurisms, loose skin, and fragile bones.
With early diagnosis and treatment consisting of daily injections of copper histidine
intraperitoneally and intrathecally to the central nervous system, some of the severe
neurological problems may be avoided and survival prolonged. However, Menkes disease
patients retain abnormal bone and connective-tissue disorders and show mild to severe mental
retardation.[111] Even with early diagnosis and treatment, Menkes disease is usually fatal.
Ongoing research into Menkes disease is leading to a greater understanding of copper
homeostasis,[113] the biochemical mechanisms involved in the disease, and possible ways to
treat it.[114] Investigations into the transport of copper across the blood/brain barrier, which are
based on studies of genetically altered mice, are designed to help researchers understand the
root cause of copper deficiency in Menkes disease. The genetic makeup of "transgenic mice"
is altered in ways that help researchers garner new perspectives about copper deficiency. The
research to date has been valuable: genes can be 'turned off' gradually to explore varying
degrees of deficiency.
Researchers have also demonstrated in test tubes that damaged DNA in the cells of a Menkes
patient can be repaired. In time, the procedures needed to repair damaged genes in the human
body may be found.

Wilson's disease
Wilson's disease is a rare autosomal (chromosome 13) recessive genetic disorder of copper
transport that causes an excess of copper to build up in the liver.[113][115][116] This results in liver
toxicity, among other symptoms.[117] The disease is now treatable.
Wilson's disease is produced by mutational defects of a protein that transports copper from
the liver to the bile for excretion.[113] The disease involves poor incorporation of copper into
ceruloplasmin and impaired biliary copper excretion and is usually induced by mutations
impairing the function of the Wilson copper ATPase. These genetic mutations produce copper
toxicosis due to excess copper accumulation, predominantly in the liver and brain and, to a
lesser extent, in kidneys, eyes, and other organs.
The disease, which affects about 1/30,000 infants of both genders,[9] may become clinically
evident at any time from infancy through early adulthood. The age of onset of Wilson's
disease ranges from 3 to 50 years of age. Initial symptoms include hepatic, neurologic, or
psychiatric disorders and, rarely, renal, skeletal, or endocrine symptomatology. The disease
progresses with deepening jaundice and the development of encephalopathy, severe clotting
abnormalities, occasionally associated with intravascular coagulation, and terminal renal
insufficiency. A peculiar type of tremor in the upper extremities, slowness of movement, and
changes in temperament become apparent. Kayser-Fleischer rings, a rusty brown
discoloration at the outer rims of the iris due to copper deposition noted in 90% of patients,
become evident as copper begins to accumulate and affect the nervous system.[118]
Almost always, death occurs if the disease is untreated.[59] Fortunately, identification of the
mutations in the Wilson ATPase gene underlying most cases of Wilson's disease has made
DNA testing for diagnosis possible.
If diagnosed and treated early enough, patients with Wilson's disease may live long and
productive lives.[114] Wilson's disease is managed by copper chelation therapy with Dpenicillamine (which picks up and binds copper and enables patients to excrete excess copper
accumulated in the liver), therapy with zinc sulfate or zinc acetate, and restrictive dietary
metal intake, such as the elimination of chocolate, oysters, and mushrooms.[59] Zinc therapy is
now the treatment of choice. Zinc produces a mucosal block by inducing metallothionein,
which binds copper in mucosal cells until they slough off and are eliminated in the feces.[119]
and it competes with copper for absorption in the intestine by DMT1 (Divalent Metal
transporter 1). More recently, experimental treatments with tetrathiomolybdate showed
promising results. Tetrathiomolybdate appears to be an excellent form of initial treatment in
patients who have neurologic symptoms. In contrast to penicillamine therapy, initial
treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic
deterioration.[120]
Over 100 different genetic defects leading to Wilson's disease have been described and are
available on the Internet at [2]. Some of the mutations have geographic clustering.[121]
Many Wilson's patients carry different mutations on each chromosome 13 (i.e., they are
compound heterozygotes).[59] Even in individuals who are homozygous for a mutation, onset
and severity of the disease may vary.[122][123] Individuals homozygous for severe mutations

(e.g., those truncating the protein) have earlier disease onset. Disease severity may also be a
function of environmental factors, including the amount of copper in the diet or variability in
the function of other proteins that influence copper homeostasis.
It has been suggested that heterozygote carriers of the Wilson's disease gene mutation may be
potentially more susceptible to elevated copper intake than the general population.[124] A
heterozygotic frequency of 1/90 people has been estimated in the overall population.[9]
However, there is no evidence to support this speculation.[125] Further, a review of the data on
single-allelic autosomal recessive diseases in humans does not suggest that heterozygote
carriers are likely to be adversely affected by their altered genetic status.
Other copper-related hereditary syndromes
Other diseases in which abnormalities in copper metabolism appear to be involved include
Indian childhood cirrhosis (ICC), endemic Tyrolean copper toxicosis (ETIC), and idiopathic
copper toxicosis (ICT), also known as non-Indian childhood cirrhosis. ICT is a genetic
disease recognized in the early twentieth century primarily in the Tyrolean region of Austria
and in the Pune region of India.[59]
ICC, ICT, and ETIC are infancy syndromes that are similar in their apparent etiology and
presentation.[126] Both appear to have a genetic component and a contribution from elevated
copper intake.
In cases of ICC, the elevated copper intake is due to heating and/or storing milk in copper or
brass vessels. ICT cases, on the other hand, are due to elevated copper concentrations in
water supplies.[9][127] Although exposures to elevated concentrations of copper are commonly
found in both diseases, some cases appear to develop in children who are exclusively
breastfed or who receive only low levels of copper in water supplies.[128] The currently
prevailing hypothesis is that ICT is due to a genetic lesion resulting in impaired copper
metabolism combined with high copper intake. This hypothesis was supported by the
frequency of occurrence of parental consanguinity in most of these cases, which is absent in
areas with elevated copper in drinking water and in which these syndromes do not occur.[128]
ICT appears to be vanishing as a result of greater genetic diversity within the affected
populations in conjunction with educational programs to ensure that tinned cooking utensils
are used instead of copper pots and pans being directly exposed to cooked foods. The
preponderance of cases of early childhood cirrhosis identified in Germany over a period of 10
years were not associated with either external sources of copper or with elevated hepatic
metal concentrations[129] Only occasional spontaneous cases of ICT arise today.
Cancer

Cancer is a complicated disease that is not well understood. Some researchers are
investigating the possible role of copper in angiogenesis associated with different types of
cancers.[130] A copper chelator, tetrathiomolybdate, which depletes copper stores in the body,
is under investigation as an anti-angiogenic agent in pilot[131] and clinical trials.[132] The drug
may inhibit tumor angiogenesis in hepatocellular carcinoma, pleural mesothelioma, colorectal
cancer, head and neck squamos cell carcinoma, breast cancer, and kidney cancer.[133] The

copper complex of a synthetic salicylaldehyde pyrazole hydrazone (SPH) derivative induced

human umbilical endothelial cell (HUVEC) apoptosis and showed anti-angiogenesis effect in
vitro.[134]
The trace element copper had been found promoting tumor growth.[135][136] Several evidence
from animal models indicates that tumors concentrate high levels of copper. Meanwhile, extra
copper has been found in some human cancers.[137][138] Recently, therapeutic strategies
targeting copper in the tumor have been proposed. Upon administration with a specific
copper chelator, copper complexes would be formed at a relatively high level in tumors.
Copper complexes are often toxic to cells, therefore tumor cells were killed, while normal
cells in the whole body remained alive for the lower level of copper.[139]
Some copper chelators get more effective or novel bioactivity after forming copper-chelator
complexes. It was found that Cu2+ was critically needed for PDTC induced apoptosis in HL60 cells.[140] The copper complex of salicylaldehyde benzoylhydrazone (SBH) derivatives
showed increased efficacy of growth inhibition in several cancer cell lines, when compared
with the metal-free SBHs.[141][142][143]
SBHs can react with many kinds of transition metal cations and thereby forming a number of
complexes.[143][144][145] Copper-SBH complexes were more cytotoxic than complexes of other
transitional metals (Cu > Ni > Zn = Mn > Fe = Cr > Co) in MOLT-4 cells, an established
human T-cell leukemia cell line. SBHs, especially their copper complexes appeared to be
potent inhibitors of DNA synthesis and cell growth in several human cancer cell lines, and
rodent cancer cell lines.[141][142]
Salicylaldehyde pyrazole hydrazone (SPH) derivatives were found to inhibit the growth of
A549 lung carcinoma cells.[146] SPH has identical ligands for Cu2+ as SBH. The Cu-SPH
complex was found to induce apoptosis in A549, H322 and H1299 lung cancer cells.
Contraception with copper IUDs

Main articles: IUD with copper and Paragard

A copper intrauterine device (IUD) is a type of long-acting reversible contraception that is
considered to be one of the most effective forms of birth control.[148] It is also considered the
most effective non-hormonal contraceptive device. The copper IUD's primary mechanism of
action is to prevent fertilization. Active substances released from the IUD, together with
products derived from the inflammatory reaction present in the luminal fluids of the genital
tract, are toxic for spermatozoa and oocytes, preventing the encounter of healthy gametes and
the formation of viable embryos.