In our patient, the low ceruloplasmin is compatible with the diagnosis of Wilson's disease. Wilson's disease is associated with low serum ceruloplasmin because of an abnormal ATPase that is required for copper to enter the secretory pathway, bind to apoceruloplasmin, and exit into the plasma bound to ceruloplasmin. Approximately 90% of all patients (85% of individuals with hepatic manifestations alone) have ceruloplasmin levels below normal.^[4] The level is relatively lower in patients with neurologic or psychiatric disease.^[5] Low-normal levels (20-22 mg/dL) are found in 5% to 15% of patients with Wilson's disease for 2 reasons: (1) ceruloplasmin is an acute-phase reactant and therefore may increase because of infection or inflammation; and (2) rather than measuring oxidase activity, some laboratories use immunologic assays that measure both ceruloplasmin and apoceruloplasmin in the serum.^[1] Pregnancy or exogenous estrogens may also elevate otherwise low ceruloplasmin levels into the normal range. False positives (ie, low ceruloplasmin levels) can occur in patients with nephrotic syndrome, protein-losing enteropathy, malabsorption, or severe malnutrition, as well as in patients with nonwilsonian fulminant hepatic failure, secondary to diminished hepatic synthetic function. Also, 10% of individuals who are heterozygous for Wilson's disease have low ceruloplasmin levels.^[4]

Our patient had a very low total serum copper level, which is typical of patients with Wilson's disease. However, serum copper measurements can be difficult to interpret. Total serum copper is the sum of ceruloplasmin copper (90%) and nonceruloplasmin copper (about 10%). Nonceruloplasmin copper (which is its potentially toxic form because of free availability for cellular uptake) is derived by subtracting the ceruloplasmin copper level (3 mcg/L x the serum ceruloplasmin concentration) from the total serum copper level.^[5] In Wilson's disease, total serum copper is decreased (mirroring decreased ceruloplasmin level), but nonceruloplasmin copper is increased. Perhaps the most useful aspect of nonceruloplasmin copper level is in following its reduction in response to chelation therapy.^[1]

Urinary copper excretion is > 100 mcg/day (normal < 50 mcg/day) in most patients with symptomatic Wilson's disease, reflecting increased serum levels of readily filterable nonceruloplasmin copper. The latter may exceed 1000 mcg/day in patients with fulminant hepatic failure as hepatic copper stores are released into the systemic circulation. However, this test is often hampered by incomplete collections or by collection in copper-containing vessels. The assay may be normal in patients with asymptomatic Wilson's disease and is therefore not a useful screening test in isolation. Moreover, the level may be elevated in other hepatic diseases, including cirrhosis, chronic active hepatitis, and cholestatic disorders such as primary biliary cirrhosis. Urinary copper measurements are used to monitor chelation therapy in Wilson's disease. If a patient is taking the chelation agents appropriately, urinary copper excretion should increase dramatically above baseline.^[4]

Our patient's liver biopsy was done by the transjugular route and did not allow enough tissue for quantification of copper concentration. Hepatic copper can be measured quantitatively from a liver biopsy specimen. The normal concentration ranges from 15-55 mcg/g dry liver. Most untreated individuals with Wilson's disease have increased hepatic copper levels, usually above 250 mcg/g dry liver. The finding of a normal hepatic copper concentration usually excludes the diagnosis of untreated Wilson's disease. However, some patients with hepatic failure have normal levels of hepatic copper, and this finding may be related to sampling error or to performing the biopsy at a time when hepatocellular necrosis has discharged most of the hepatic copper to other tissues.^[8] However, false positives above 250 mcg/g occur in other chronic cholestatic disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, extrahepatic biliary obstruction or atresia, intrahepatic cholestasis of childhood, and idiopathic (Indian) childhood cirrhosis.^[4] A key biochemical difference is that in all other disorders of chronic cholestasis, the ceruloplasmin level is normal or increased, suggesting a defect in biliary copper excretion past the point of entry into the secretory pathway.^[2,4]