What are the causes of low ceruloplasmin levels?

Causes of Low Ceruloplasmin Levels

Low ceruloplasmin levels occur in multiple conditions beyond Wilson's disease, including severe end-stage liver disease, protein-losing conditions (renal or enteric), malabsorption syndromes, heterozygous ATP7B carriers, and familial aceruloplasminemia. 1

Wilson's Disease

• Wilson's disease is the most clinically significant cause of low ceruloplasmin, though it accounts for only 5.9-11.1% of cases with low levels in unselected populations. 2, 3
• Ceruloplasmin is typically <0.1 g/L in Wilson's disease, though 15-36% of children with confirmed Wilson's disease have normal ceruloplasmin levels. 1, 4
• The mechanism involves decreased ceruloplasmin gene transcription (reduced to 44% of normal) and decreased mRNA levels (33% of controls), not just impaired copper incorporation. 5
• Ceruloplasmin alone has only a 6% positive predictive value for Wilson's disease, making it insufficient as a standalone diagnostic test. 1, 4

Hepatic Causes

• Severe end-stage liver disease of any etiology causes low ceruloplasmin due to impaired hepatic synthetic function. 1
• Specific liver conditions associated with low ceruloplasmin include:
  • Autoimmune hepatitis 1
  • Acute viral hepatitis 2
  • Chronic hepatitis (particularly viral hepatitis B and C, which account for 53% of non-Wilson's hypoceruloplasminemia cases) 6
  • Alcoholic liver disease 2
  • Drug-induced liver disease 2
• Cholestatic liver diseases (sclerosing cholangitis) can mimic Wilson's disease with initially low ceruloplasmin that normalizes on follow-up. 7

Protein Loss and Malabsorption

• Marked renal protein loss causes urinary ceruloplasmin wasting. 1
• Enteric protein loss results in gastrointestinal losses of ceruloplasmin. 1
• Malabsorption syndromes, including celiac disease, lead to decreased ceruloplasmin levels. 1, 2

Genetic Causes (Non-Wilson's)

• Heterozygous carriers of ATP7B mutations (approximately 20% of heterozygotes) may have decreased ceruloplasmin levels without copper overload disease. 1, 8
• Familial aceruloplasminemia is characterized by complete absence of ceruloplasmin protein, causing hemosiderosis (iron accumulation) but not copper accumulation. 1
• When ceruloplasmin falls below 1-5% of normal in aceruloplasminemia, impaired ferroxidase activity causes iron deficiency anemia. 8

Important Diagnostic Pitfalls

• Ceruloplasmin is an acute phase reactant: inflammation in the liver or elsewhere can elevate levels to the normal range, masking Wilson's disease. 1, 8
• Hyperestrogenemia (pregnancy, estrogen supplementation) elevates ceruloplasmin levels. 8
• Immunologic assays may overestimate ceruloplasmin by detecting apoceruloplasmin (copper-free form). 8
• The predictive value of ceruloplasmin is particularly poor in acute liver failure. 8, 4

Essential Follow-Up Testing

When low ceruloplasmin is detected, use the Leipzig Diagnostic Scoring System rather than relying on ceruloplasmin alone. 1 Essential additional tests include:

• Slit-lamp examination for Kayser-Fleischer rings 1
• 24-hour urinary copper excretion (>100 μg/24h suggests Wilson's disease; cholestatic mimickers typically have levels around 74.5 μg/day versus 322.3 μg/day in true Wilson's disease) 1, 7
• Non-ceruloplasmin-bound copper (free copper) calculation 1
• Hepatic copper quantification (>250 mcg/g dry weight is abnormal) 1, 9
• ATP7B genetic testing 1
• Serial ceruloplasmin measurements: normalization on follow-up suggests a non-Wilson's cause such as cholestatic liver disease. 7