What effect does a decrease in ceruloplasmin (Cp) levels have on free copper levels?

Effect of Decreased Ceruloplasmin on Free Copper Levels

When ceruloplasmin decreases, free (non-ceruloplasmin-bound) copper levels increase, as the reduced carrier protein capacity leaves more unbound copper circulating in the blood. 1

Mechanism and Relationship

The relationship between ceruloplasmin and free copper is inversely proportional:

• Ceruloplasmin normally binds approximately 90% of circulating copper, with each molecule carrying 6 copper atoms (holoceruloplasmin). 1
• When ceruloplasmin levels fall, total serum copper typically decreases proportionally, but the concentration of copper not bound to ceruloplasmin (free copper) paradoxically increases. 1
• Normal or elevated total serum copper in the face of decreased ceruloplasmin indicates a significant increase in free copper concentration. 1

Clinical Calculation

Free copper can be quantified using this formula:

• Free copper (µg/L) = Total serum copper (µg/L) - (3.15 × ceruloplasmin in mg/L). 1
• In most untreated Wilson's disease patients with low ceruloplasmin, free copper is elevated above 200 µg/L (normal is approximately 150 µg/L or 15 µg/dL). 1

Clinical Significance

The elevation of free copper when ceruloplasmin is low has important implications:

• Free copper is the toxic, biologically active form that can cause oxidative damage to tissues, particularly in the liver, brain, and kidneys. 1
• Elevated free copper drives increased urinary copper excretion, as the 24-hour urinary copper reflects the amount of non-ceruloplasmin-bound copper in circulation. 1
• In Wilson's disease, baseline urinary copper excretion is typically greater than 1.6 µmol/24h (100 µg/24h) due to elevated free copper. 1

Important Caveats

Several clinical scenarios complicate this relationship:

• In acute liver failure from any cause (including Wilson's disease), serum copper may be markedly elevated due to sudden release from hepatic tissue stores, further increasing free copper despite low ceruloplasmin. 1
• Elevated free copper is not specific to Wilson's disease and can occur in acute liver failure of any etiology, chronic cholestasis, and copper intoxication. 1
• The accuracy of calculated free copper depends entirely on the quality of both serum copper and ceruloplasmin measurements, making it more valuable for monitoring treatment than diagnosis. 1

Treatment Monitoring Context

During Wilson's disease treatment:

• Target free serum copper should be <10 µg/dL to indicate adequate copper chelation. 2, 3
• Excessively low free copper (<5 µg/dL) combined with very low 24-hour urinary copper may signal systemic copper depletion, a complication of overzealous treatment. 1