Can elevated ferritin (iron) levels cause low ceruloplasmin (copper) levels?

High Ferritin Does Not Cause Low Ceruloplasmin

No, elevated ferritin (iron) levels do not cause low ceruloplasmin (copper) levels. These are independent biomarkers reflecting different metabolic pathways, and their alterations typically indicate distinct underlying pathologies rather than a direct causal relationship.

Understanding the Biological Relationship

Ceruloplasmin and ferritin measure fundamentally different systems:

• Ceruloplasmin is a copper-carrying protein synthesized in the liver that functions as a ferroxidase, oxidizing ferrous iron to ferric iron for binding to transferrin 1
• Ferritin is an iron storage protein and acute phase reactant that rises with inflammation, iron overload, liver disease, and cellular damage 1
• While ceruloplasmin has ferroxidase activity that facilitates iron metabolism, iron status does not regulate ceruloplasmin expression 2

Evidence Against Causation

Animal studies definitively show iron does not control ceruloplasmin production:

• Rats with severe iron deficiency (hematocrits half normal, no detectable liver ferritin) showed no alteration in hepatic ceruloplasmin mRNA expression or circulating ceruloplasmin levels 2
• Iron supplementation (25 mg iron dextran) increased liver ferritin but did not alter liver ceruloplasmin mRNA expression or circulating ceruloplasmin levels 2
• The study concluded that "iron status is not an important factor in the expression of plasma ceruloplasmin made by the liver" 2

When Both Are Abnormal: Look for Separate Causes

If you encounter both high ferritin and low ceruloplasmin, investigate distinct etiologies:

Low Ceruloplasmin Causes:

• Wilson disease (copper overload disorder with ATP7B mutations) - ceruloplasmin typically <200 mg/L 1
• Aceruloplasminemia (ceruloplasmin gene mutations on chromosome 3) - patients exhibit hemosiderosis but not copper accumulation 1
• Severe end-stage liver disease of any etiology 1
• Marked renal or enteric protein loss 1
• Heterozygote carriers - approximately 20% of Wilson disease heterozygotes have decreased ceruloplasmin 1

High Ferritin Causes:

• Inflammation/infection - ferritin is an acute phase reactant 1, 3
• Chronic alcohol consumption, NAFLD, metabolic syndrome - account for >90% of hyperferritinemia cases 3
• Necroinflammatory liver disease (alcoholic liver disease, chronic hepatitis B/C, NAFLD) 1
• Malignancy (lymphomas, solid tumors) 1, 3
• Hereditary hemochromatosis (HFE mutations) - but only when transferrin saturation ≥45% 1

Special Case: NAFLD with Ceruloplasmin Variants

Recent research identifies a genetic link in NAFLD patients, but this is correlation, not causation:

• Ceruloplasmin gene variants are associated with hyperferritinemia and increased hepatic iron stores in NAFLD patients 4
• Carriers of ceruloplasmin variants had independently associated hyperferritinemia (adjusted OR 5.99; 95% CI 1.83-19.60) and more severe liver fibrosis 4
• This represents genetic predisposition affecting both systems, not high ferritin causing low ceruloplasmin 4
• In NASH patients, low serum ceruloplasmin and high serum ferritin are correlated (AUC 0.80 and 0.81 respectively for predicting NAS ≥5), with ceruloplasmin negatively correlated with ferritin 5

Clinical Approach When Both Are Abnormal

Follow this algorithmic evaluation:

1. Measure transferrin saturation alongside ferritin - if TS <45%, iron overload is unlikely and secondary causes predominate 1, 3

2. For low ceruloplasmin (<200 mg/L):

   • Check 24-hour urinary copper excretion (>1.6 µmol/24h suggests Wilson disease) 1
   • Perform slit-lamp examination for Kayser-Fleischer rings 1
   • Consider ATP7B genetic testing if Wilson disease suspected 1
   • Assess for severe liver disease, protein-losing conditions 1

3. For high ferritin:

   • Rule out inflammation (check CRP, ESR) 3
   • Assess for chronic alcohol use, metabolic syndrome, NAFLD 3
   • If TS ≥45%, proceed with HFE genetic testing 1, 3
   • Consider liver imaging or biopsy if ferritin >1000 µg/L with abnormal liver enzymes 1

Critical Pitfalls to Avoid

• Never assume high ferritin causes low ceruloplasmin - they reflect independent pathophysiologic processes 2
• Do not use ferritin alone to diagnose iron overload - always check transferrin saturation 1, 3
• Recognize ceruloplasmin is also an acute phase reactant - it can be elevated by inflammation, pregnancy, estrogen supplementation 1
• Remember that extremely low ceruloplasmin (<50 mg/L) strongly suggests Wilson disease, requiring urgent evaluation 1