Ceruloplasmin

What sample is needed for Ceruloplasmin?

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

What are the precautions for Ceruloplasmin?

• Avoid lipemic and hemolyzed samples.

What are the Indications for Ceruloplasmin?

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

How will you define 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.

How will you discuss the pathophysiology of Ceruloplasmin?

1. Ceruloplasmin is an alpha-2 globulin.
2. The concentration at birth gradually increases to the adult level and continues to rise slowly 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 characterized by a decreased level of ceruloplasmin.
   1. In low Ceruloplasmin, increased unbound copper is toxic to tissues.

What are the functions of Ceruloplasmin?

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, specifically by oxidizing Fe++ to Fe+++ and preventing the formation of toxic iron compounds.

How will you discuss the 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 Ceruloplasmin, which is produced by the liver.
   2. In the case of a 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.
   2. 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 a 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.

Discuss the Copper absorption and excretion?

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

What are the Copper functions?

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

What are the sites where Copper can deposit?

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.

What are the effects of Copper deficiency?

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 the arteries in the brain.
    3. Urinary copper excretion is increased.

What is 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):

How will you discuss the 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 parents.
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 begins to accumulate 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.
14. Wilson’s disease is characterized by the inability of the liver to make a normal quantity of Ceruloplasmin.
15. Ceruloplasmin is an α-2 globulin that transports copper.

What is the etiology of Wilson’s disease?

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

What will be the clinical presentation of Wilson’s disease?

1. The triad of the S/S and diagnostic of Wilson’s disease is:
   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. Approximately 30% to 40% of individuals develop neurological symptoms.
   3. About 20% to 30% develop psychiatric abnormalities like schizophrenia.
3. Few patients develop Coombs-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 patient group.
5. Some patients present with minimal active or inactive cirrhosis.
6. Neurological symptoms start from the basal ganglia area (lentiform nucleus) of the brain, and they consist 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, a lack of appetite, and abdominal pain.
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).
    4. It is grossly visible but sometimes needs slit-lamp examination.
    5. Approximately 20% of patients may not exhibit Kayser-Fleischer rings at the time of diagnosis.
    6. 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.

How will you diagnose Wilson’s disease?

Clinical diagnostic features are:

1. Kayser-Fleischer ring. It may be apparent to the naked eye or sometimes require a slit-lamp examination.
2. Liver cirrhosis.
3. Neurological features.

Laboratory findings:

1. There is increased urinary excretion of copper, >40 µg/24 hours, and usually it is >100 µg/24 hours.
2. Advise serum or plasma copper levels.
   1. Hepatic copper is raised >210 to 250 µg (dry liver).
   2. The total serum copper level is decreased, but the direct react fraction is elevated.
   3. Urinary excretion of copper is increased.
3. Ceruloplasmin level. This is low, <20 mg/dL.
   1. <5 mg/dL is diagnostic.
4. Hemolytic anemia is Coombs-negative.
5. Measuring superoxide dismutase and cytochrome oxidase in platelets or leukocytes helps assess copper status.