Ceruloplasmin

Sample for Ceruloplasmin

1. Venous blood is needed to prepare the serum.
2. Fresh serum is preferred.
3. It can store at 4 °C for 3 days.
4. It can be kept at -20 °C for 4 weeks.

Precaution for Ceruloplasmin

• Avoid lipemic and hemolyzed samples.

Purpose of the test (Indications) for Ceruloplasmin

1. This is an acute-phase protein.
2. This test is done to diagnose Wilson’s disease.

Definition of Ceruloplasmin

1. Ceruloplasmin is a copper-containing, α2-glycoprotein with enzymatic activities like copper oxidase, histaminase, and ferrous oxidase.
2. It is synthesized in the liver, where 6 to 8 atoms of copper, half as Cu⁺ and half as Cu⁺⁺ ions, are attached to an apo-ceruloplasmin.

Pathophysiology of Ceruloplasmin

1. Ceruloplasmin is alpha-2 globulin.
2. Low concentration at birth gradually increases to the adult level and slowly increases with age.
3. Adult females have higher levels than males.
4. Its half-life is 4.5 days, and its molecular weight is 132,000 daltons.
   1. It contains 90% to 95% of serum copper, giving it a blue color.
   2. In the case of increased Ceruloplasmin, the plasma has a greenish tint.
   3. Its primary role is oxidation and reduction in the plasma.

5. Ceruloplasmin will bind copper for transport in the blood.
6. Ceruloplasmin is synthesized in the liver.

7. Wilson’s disease is an inherited disorder where ceruloplasmin level is decreased.
8. In low Ceruloplasmin, increased unbound copper is toxic to tissues.

Ceruloplasmin functions:

1. Ceruloplasmin’s physiological role is reduction and oxidation (Redox).
2. This may be an oxidant or antioxidant, depending upon the factor, such as the presence of free Ferric (Fe⁺⁺⁺) ions and ferritin-binding sites.
3. Ceruloplasmin is essential for maintaining the ionic state of iron, in particular, oxidizing Fe⁺⁺ to Fe⁺⁺⁺ and preventing the formation of toxic iron products.

Copper metabolism:

1. Copper is absorbed from the gastrointestinal system in food.
2. 1.5 to 3 mg/day of dietary copper is safe and adequate for the body.
   1. Excess copper is excreted into the bile by the Ceruloplasmin, which is produced by the liver.
   2. In the case of deficiency of Ceruloplasmin, copper accumulates in the body.
   3. Ceruloplasmin is a copper-containing protein that accounts for more than 95% of the copper found in the plasma.
3. Copper is bound to Ceruloplasmin (α-2 globulin) with ferroxidase activity.
   1. Copper is also transported in plasma loosely bound to albumin.
      1. A small fraction of the copper is complexed with amino acids.
4. Excretion of copper occurs mainly in the bile and a small fraction in the urine (<40 µg/day).
5. Plasma copper is not a reliable indicator of blood copper level.
6. Factors that will give the raised level of copper are:
   1. Oral contraceptives.
   2. Pregnancy.
   3. Inflammation or infectious process.
7. Sources of copper:
   2. Liver.
   3. Kidneys.
   4. Eggs.
   5. Shellfish.
   6. Legumes.

Copper absorption and excretion:

1. Dietary copper of 1.5 to 3.0 mg/day is the requirement.
2. It is absorbed in the intestine, and a small amount of blood binds albumin and mostly Ceruloplasmin.
3. It is excreted in the feces.
4. <3% is lost in the urine and copper.

Copper functions:

• It is involved in the development of:

1. Nerves.
2. Bones. Copper maintains healthy bones. It prevents osteoporosis.
3. Skin pigments.
4. Collagen.
5. It helps the immune system.
6. It contributes to iron absorption.
7. It prevents cardiovascular diseases.
8. It prevents osteoporosis.
9. Copper is a metal component of various enzymes:
   1. Cytochrome oxidase.
   2. Superoxide dismutase.
   3. Tyrosinase.

Copper can deposit in:

1. Eye.
2. Liver.
3. Brain.
4. Kidneys.
5. Hemolysis, necrosis, and other cellular changes may be caused by lipid peroxidation, a known toxic effect of copper.
6. Copper is essential for the normal folding of the polypeptide chain.

Copper deficiency is associated with:

1. Heart diseases.
2. Bone and joint osteoarthritis,
3. Osteoporosis.
4. Demineralization is also associated with copper deficiency.
5. Microcytic and hypochromic anemia.
6. There is neutropenia.
7. There may be hypothermia.
8. There is hypercholesterolemia.
9. There is decreased protection of the antioxidants.
10. Copper deficiency is also associated with cerebellar and cerebral degeneration.
    1. There may be a subdural hematoma.
    2. There may be thrombosis of arteries in the brain.
    3. Urinary copper excretion is increased.

The normal level of Ceruloplasmin

Source 1

1. Adult = 23 to 50 mg/dL (230 to 500 mg/L).
2. Neonates = 2 to 13 mg/dL (20 to 130 mg/L).
3. >7 years  =  20 to 54 mg/dL

Source 2

Wilson’s disease (Hepatolenticular degeneration):

Pathophysiology of Wilson’s disease:

1. Wilson’s disease is a familial disorder of copper metabolism, and it is transmitted as an autosomal recessive trait.
   1. It is inherited as an autosomal recessive trait.
2. This is also known as hepatolenticular degeneration and progressive lenticular degeneration.
3. Worldwide, it is 1 in 30,000 people.
4. Age: Most people diagnosed are between the ages of 5 to 35 years (another reference is 8 to 30 years) but may be seen in younger and older people (another source = This disease occurs from 6 to 40 years).
   1. The symptoms do not appear before the age of 6 years.
5. This is a rare genetic disease with an accumulation of copper (copper toxicity).
   1. The patient inherits one defective gene from one of the couples.
6. Excessive accumulation of copper in the liver, brain, kidneys, and cornea.
7. There is a decrease in copper-containing Ceruloplasmin in the liver.
8. There is an impairment of the excretion of copper from the liver.
9. Copper starts accumulating in the brain and liver.
10. Ceruloplasmin level may be as low as <20 mg/dL. These levels are typically low at 10 mg/dL.
11. Albumin-bound and free copper levels are increased, but total serum copper is low because of low Ceruloplasmin.
12. It can be controlled if diagnosed before the deposition of copper in tissue.
13. There is an accumulation of copper in the liver, kidney, brain, and cornea.

Pathogenesis of Wilson’s disease:

1. Wilson’s disease is characterized by the inability of the liver to make a normal quantity of Ceruloplasmin.
2. Ceruloplasmin is α-2 globulin that transports copper.

The etiology of Wilson’s disease:

1. The etiology is unknown; there is excessive deposition of copper in various tissues, and it ultimately produces damage to the basal ganglia of the brain and liver tissue.
2. Kidneys may also be affected by producing amino aciduria.
3. Copper is also deposited in the cornea, producing a zone of discoloration called the Kayser-Fleischer ring.

Clinical presentation of Wilson’s disease:

1. Triad of the S/S and diagnostic of Wilson’s diseases are:
   1. Typical basal ganglia symptoms.
   2. Kayser-Fleischer  ring.
   3. Hepatic cirrhosis.
2. The patient has symptoms of:
   1. About 30% to 50% of the patients develop liver symptoms.
   2. About 30% to 40% develop neurological symptoms.
   3. About 20% to 30% develop psychiatric abnormalities like schizophrenia.
3. Few patients develop Coomb’s negative hemolytic anemia.
4. Children are usually seen with liver symptoms. Mostly, there is chronic hepatitis.
   1. Macronodular cirrhosis develops later and is usually found in the late-age patients group.
5. Some patients present with minimal active or non-active cirrhosis.
6. Neurological symptoms start from the basal ganglia area (lentiform nucleus) of the brain, and it consists of:
   1. Varying degrees of incoordination.
   2. Tremors.
   3. Spasticity.
   4. Rigidity.
   5. Dysarthria (speech problems)
   6. There may be flapping tremors.
7. There is fatigue, lack of appetite, and pain in the abdomen.
8. Hepatitis.
9. Cirrhosis.
10. Recurrent neuromuscular incoordination.
    1. Uncontrolled movements or muscle stiffness.
    2. Swallowing problems.
    3. Green-brown discoloration in the cornea due to the deposition of copper (Kayser-Fleischer rings).
       1. It is grossly visible but sometimes needs slit-lamp examination.
       2. 20% of the patients may not show Kayser-Fleischer rings at the time of diagnosis.
    4. Urinary copper excretion is increased.
11. Early detection is the key to controlling the disease.
12. Ceruloplasmin is an acute-phase protein that will be raised in infections, stress, and pregnancy.