COPPER

Copper metabolism and
investigation of its disorders
• Prof Roy Sherwood

• Consultant Clinical Scientist & Scientific Director, Viapath
• Professor of Clinical Biochemistry, KCL
• King’s College Hospital
Copper
Essential trace element.
Co-factor for:
cytochrome c oxidase lysyl oxidase
dopamine B hydroxylase tyrosinase
superoxide dismutase caeruloplasmin
Oxidative properties
generation of metal dependent oxyradicals
competition with other metal ions
Copper metabolism
Body stores - 100-150 mg

Intake - 2-3 mg daily
Absorbed copper is stored in the liver bound to
metallothionen and caeruloplasmin.
Caeruloplasmin is the carrier protein in the
circulation although copper may be bound to
albumin or other proteins.
Urinary copper excretion is low, therefore most of
the copper is excreted into the bile.
Copper uptake in intestine
• hCTr1 is a heavily glycosylated plasma
membrane transporter (190 aas)
• DMT1 can also transport Cu
• ATP7A probably transports Cu from
mucosal cells to blood
• Competition occurs between Cu, Zn and Fe
for transport
Copper associated disorders
Menkes disease
Tissue copper deficiency. X-linked
Gene (ATP7a) codes for an ATPase metal ion transporter
Wilson’s disease
Copper toxicity to liver and brain. Autosomal recessive.
Gene (ATP7b) on chromosome 13 codes for a different
ATPase metal ion transporter.
Prevalence 1 in 30,000
Copper associated diseases of childhood
Indian childhood cirrhosis
Non-Indian childhood cirrhosis
Acaeruloplasminaemia
Copper deficiency
• Microcytic hypochromic anaemia
• Neutropenia
• Neurological effects in neonates
• Collagen synthesis
• Myelopathy
• Antioxidant activity
– Lipoproteins
– Catecholamine metabolism
– Vascular effects
Copper deficiency
• Nutritional deficiency
– Kwashiokor, TPN, diarrhoeal illness, coeliac disease,
excess Zn supplements
• Excessive loss
– Crohn’s disease and other causes of blood loss
• Menke’s disease
– ATP7A - 17 domains, 6 Cu binding, 8 transmembrane,
phosphatase, phosphorylation & ATP binding sites
– Decreased Cu in plasma, brain & liver but increased in
kidney, spleen & skeletal muscle
Menkes disease
• X linked - only males affected
• Kinky hair of Steely hair syndrome
• Severe neurological damage
– Fits
– Typical appearance
– Invariably fatal
– Diagnosis depends on demonstration of low uptake of
copper into cells
• Damage occurs in utero
– Prenatal diagnosis: iv Cu treatment can be effective if
started before term
Case report - Menkes
• A 5 month old male child presented with fits and
failure to thrive
• On examination the child had the typical facial
appearance pili torti in the hair and floppy limbs.
Low plasma Cu and caeruloplasmin with a normal
urine Cu.
• Confirmation of the diagnosis: decreased Cu
uptake by fibroblasts
• Treated with daily injections of Cu histidinate.
Gave normal plasma copper and caeruloplasmin
but no improvement in mental function
Wilson’s disease
Presentation: hepatic 45%, neurological 45%,
psychiatric 10%
Hepatic: In childhood - fulminant failure,
haemolytic anaemia, encephalopathy
In older patient - cirrhosis/hepatitis
Neurological: Tremor, speech difficulties, dysphagia,
movement disorders
Psychiatric: Mood swings, depression, frank
psychosis
Pili torti
Investigation of Wilson’s disease
Serum copper and caeruloplasmin

Urinary copper excretion
Slit-lamp examiantion for Kayser-Fleischer rings
Penicillamine challenge test
Hepatic copper
Copper uptake studies
Genetics
Serum copper and caeruloplasmin
Caeruloplasmin is a 132,000 Da single-chain
glycoprotein containing 6 atoms Cu 1.e. 3 ug/mg.
Acute phase reactant increased in inflammation,
infection etc. Stimulated by steroids, therefore,
increased in pregnancy and steroid therapy.
80% of Wilson’s patients have decreased serum
copper and caeruloplasmin. In fulminant liver failure
both may be raised. 80% of heterozygotes have
normal serum copper and caeruloplasmin.
Caeruloplasmin decreased in hepatitis due to reduced
synthesis.
KF Rings
Total serum copper in children with liver disease
40
32
total serum copper (umol/L)
24
normal range
16
0
WD aCAH PSC CLD LF AH no LD
Caeruloplasmin in children with liver disease
0.75
0.60
caeruloplasmin (g/L)
0.45
normal range
0.30
0.15
0
Non-caeruloplasmin bound
copper
In conditions of copper excess there is an increase
in non-caeruloplasmin bound - ‘free’ copper.
May be calculated as follows:
Free Cu = Total Cu - caeruloplasmin (g/L) x 50.4

Serum free copper in children with liver disease
15
serum free copper (umol/L)
12
0
W aCAH PSC CLD LF AH no LD
D
Urine copper
Normal 24h urinary copper excretion is < 1.0 umol/24h.

Important, therefore, to avoid contamination.
In symptomatic patients with Wilson’s disease urine
copper is increased - median 8.2. umol/24h
Often normal in asymptomatic patients.
Obstructive liver disease may cause an increase in
urinary copper excretion.
Baseline 24h urinary copper excretion in children with liver disease
40
30
urine copper (umol/24h)
20
10

Penicillamine challenge test
Value of urinary copper excretion after penicillamine
challenge in the diagnosis of Wilson’s disease
C.Martins da Costa, D.BALDWIN, B.Portmann,

Y.Lolin, AP Mowat, G.Mieli-Vergani
Hepatology 15: 609-615 1992

Post-penicillamine 24h urinary copper excretion in children with liver disease
80
60
urine copper (umol/24 h)
40
20

Hepatic copper
Measurable by atomic absorption after nitric acid

digestion.
Normal hepatic copper is low - < 50 ug/g
May be increased in patients with PBC, PSC and
other cases of cirrhosis
Variability in copper with sampling, particularly
in cirrhosis.
Liver Copper in children with liver disease
3000
Liver copper (ug/g dry wt)
2400
1800
1200
600
Wilson’s Others
Typical results
Normal Wilson's
disease
Fulminant Non-fulminant Heterozygotes
Serum Cu 12-25 14.7 5.0 8.2
(umol/L)
Caeruloplasmin 0.2-0.45 0.11 0.08 0.17
(g/L)
Urine Cu - Pre <1.2 34 3.2 0.6
(umol/24h)
- Post <25 43 32.6 8.4
Liver Cu 20-50 880 250 103
(ug/g dry wt)
Sensitivity and specificity of tests
for Wilson’s disease
Sensitivity Specificity
% %
Caeruloplasmin 82.4 94.4
Serum copper 56.3 94.2
Urine copper 100 82.8
- Pre
Urine copper 88.2 98.2
- Post
Liver copper 75.0 61.5
Wilson’s disease gene
Wilson disease is inherited as an autosomal
recessive disease.
The gene has been located on chromosome 13
occupying 80 kb and encoding a 7.5 kb product
There is significant sequence homology (54%) with
the gene causing Menke’s disease.
The product is an ATP-dependent copper-
transporting protein (not caeruloplasmin) involved
in cellular regulation of copper.
ATP7b gene
Gene mutations
Large study involving cases from US, Russia, Sicily,
Sweden and Costa Rica (Am J Hum Genet 61 317-28 1997)
27 distinct mutations found. Compound heterozygotes
common. New mutations are continually being found (>75).
Commonest His1069Glu was represented in 38% of WD
from US, Russia and Sweden
In the Costa Ricans Asn1270Ser represented 61% of
mutations.
No obvious genotype-phenotype correlations
Treatment and monitoring
Penicillamine - Urine excretion on and
Trientine off therapy
Zinc - Urine copper not helpful
All treatments - serum copper and

caeruloplasmin
Copper diseases in childhood
Copper-associated liver disease in childhood
A Baker, S Gormally, R Saxena, D.BALDWIN, B

Drumm, B Portmann AP Mowat
J Hepatol 23: 538-543 1995

Case 1
15 month old female infant from rural Eire

2 week history of malaise, pyrexia, abdominal
swelling and jaundice.
Rapid deterioration with DIC, encephalopathy
and renal failure - transferred to King’s LITU.
Cardiac arrest at 4 weeks after onset of
symptoms whilst awaiting OLT at King’s
Case 2
2.5 year old female child from East London

2 week history of lethargy, abdominal
distention and jaundice.
Rapid deterioration with encephalopathy
leading to emergency OLT 4 weeks after
onset of symptoms
Uneventful recovery and well at 6 years of
age.
Copper studies
Case 1 Case 2 Normal
Serum Cu 54 16.9 12-25

(umol/L)
Caeruloplasmin 0.28 0.16 0.15-0.45
(g/L)
Free copper 39.9 8.9 <4
(umol/L)
Liver copper 1310 1100 <50
(ug/g)
Water copper 6.3 <0.1 <1.0
(umol/L)
Histology
Prominent Mallory’s hyaline in ballooned hepatocytes.

Orcein +ve aggregates of copper associated protein.
Micronodular cirrhosis.
Typical histological features of Indian childhood
cirrhosis.
Wilson’s - staining for copper and copper associated

protein rare.
Mallory’s hyaline less frequent.
Non-Indian childhood cirrhosis
Cases with high copper intake:
Australia - 14 m M.
Germany - 7 m F, 9 m F, 5 m F.
Ireland - 7 m M.
Cases with no excess copper intake:
US - 2 M, 6 F, 5 M, 4 M, 5 F, 14 F.
Singapore - 4 F, 4 F, 6 F, 5 M.
Italy - 10 M.
Hungary - 6 F.
3 treated successfully - rest died within 32 months

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Copper metabolism and

investigation of its disorders

• Prof Roy Sherwood

Body stores - 100-150 mg

Serum copper and caeruloplasmin

May be calculated as follows:

Free Cu = Total Cu - caeruloplasmin (g/L) x 50.4

Normal 24h urinary copper excretion is < 1.0 umol/24h.

WD aCAH PSC CLD LF AH no LD

C.Martins da Costa, D.BALDWIN, B.Portmann,

Hepatology 15: 609-615 1992

WD aCAH PSC CLD LF AH no LD

Measurable by atomic absorption after nitric acid

All treatments - serum copper and

Copper-associated liver disease in childhood

A Baker, S Gormally, R Saxena, D.BALDWIN, B

J Hepatol 23: 538-543 1995

15 month old female infant from rural Eire

2.5 year old female child from East London

Serum Cu 54 16.9 12-25

Prominent Mallory’s hyaline in ballooned hepatocytes.

Wilson’s - staining for copper and copper associated

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