What are the potential causes of high ferritin (a protein that stores iron) levels, low Total Iron-Binding Capacity (TIBC), and normal iron levels in a patient?

High Ferritin, Low TIBC, Normal Iron: Diagnostic Approach

This pattern most strongly indicates anemia of chronic disease (ACD) or anemia of inflammation, where iron is trapped in storage sites and unavailable for erythropoiesis despite adequate total body iron stores. 1

Understanding the Laboratory Pattern

The combination of elevated ferritin with low TIBC represents an inflammatory iron block rather than true iron overload 2, 1. This occurs because:

• Ferritin is an acute-phase reactant that rises during inflammation, infection, malignancy, and tissue injury independent of actual iron stores 2, 3
• Low TIBC reflects reduced transferrin synthesis during inflammatory states, occurring in chronic infection, malignancies, liver disease, and inflammatory conditions 1
• Normal serum iron with this pattern indicates iron is present but functionally unavailable for red blood cell production 1

Primary Differential Diagnosis

Most Common Causes (>90% of cases)

Inflammatory and Infectious Conditions:

• Chronic infections (bacterial, viral, fungal) 2
• Systemic inflammatory response syndrome 2
• Adult-onset Still's disease (ferritin often 4,000-30,000 ng/mL with glycosylated fraction <20%) 2
• Rheumatologic diseases 2

Liver Disease:

• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 2
• Chronic alcohol consumption 2
• Viral hepatitis B or C 2
• Acute hepatitis 2

Malignancy:

• Solid tumors 2
• Lymphomas 2
• Hepatocellular carcinoma 2

Cellular Damage:

• Muscle necrosis (rhabdomyolysis) 2
• Hepatocellular necrosis 2
• Tissue breakdown from any cause 2

Metabolic Conditions:

• Metabolic syndrome 2
• Chronic kidney disease 2

Critical Diagnostic Algorithm

Step 1: Calculate Transferrin Saturation (TSAT)

TSAT = (Serum Iron ÷ TIBC) × 100 1

• If TSAT <20%: Confirms anemia of chronic disease or functional iron deficiency 1
• If TSAT ≥45%: Consider primary iron overload (hemochromatosis) despite low TIBC being atypical 2, 4

Step 2: Measure Inflammatory Markers

Order immediately: 2, 1

• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)

Elevated inflammatory markers confirm ACD diagnosis 1

Step 3: Assess for Underlying Causes

Complete metabolic panel including: 2

• AST, ALT (hepatocellular injury)
• Albumin (synthetic function, malnutrition)
• Creatinine (kidney disease)

Additional targeted testing: 2

• Creatine kinase (CK) for muscle necrosis
• Complete blood count with differential (hematologic malignancy)
• Viral hepatitis serologies if liver enzymes elevated
• Age-appropriate cancer screening if unexplained

Step 4: Special Considerations by Ferritin Level

Ferritin 100-1,000 μg/L: 2

• Most likely secondary causes (inflammation, liver disease, metabolic syndrome)
• Focus on treating underlying condition

Ferritin >1,000 μg/L: 2

• Higher risk scenario requiring urgent evaluation
• Consider liver biopsy if abnormal liver tests present
• Rule out hemophagocytic lymphohistiocytosis, severe infection, malignancy

Ferritin >10,000 μg/L: 2

• Rarely represents simple iron overload
• Urgent specialist referral for life-threatening conditions (adult-onset Still's disease, hemophagocytic syndrome, severe sepsis)

Key Clinical Pitfalls to Avoid

Never diagnose iron overload based on ferritin alone without checking TSAT 2. In the general population, iron overload is NOT the most common cause of elevated ferritin—over 90% of cases are due to inflammation, liver disease, malignancy, or metabolic conditions 2.

Do not assume iron deficiency requires treatment in this pattern 1. The elevated ferritin with low TIBC indicates iron is present but trapped; giving additional iron will not help and may be harmful 1.

Do not overlook occult malignancy 2. Unexplained persistent hyperferritinemia warrants age-appropriate cancer screening, particularly for solid tumors and lymphomas.

Recognize functional iron deficiency in chronic kidney disease as an exception 5, 1. In CKD patients on erythropoiesis-stimulating agents, ferritin 100-700 ng/mL with TSAT <20% may respond to IV iron therapy despite the elevated ferritin 5, 1.

Management Approach

Primary treatment targets the underlying inflammatory condition, not the ferritin level itself 1. Specific interventions include:

• Inflammatory conditions: Disease-specific anti-inflammatory therapy 2
• Infections: Appropriate antimicrobial treatment 2
• NAFLD/metabolic syndrome: Weight loss, metabolic optimization 2
• Malignancy: Oncologic treatment 2

Monitor response with: 1

• Hemoglobin every 3-6 months
• Ferritin and TSAT every 3-6 months
• Inflammatory markers to assess disease activity

Consider trial of IV iron only if: 5, 1

• Chronic kidney disease with TSAT <20% despite ferritin >100 ng/mL
• Weekly IV iron 50-125 mg for 8-10 doses can distinguish functional iron deficiency (responds with hemoglobin increase) from pure inflammatory block (no response) 5