Can Ehlers-Danlos syndrome cause elevated ferritin levels?

Can Ehlers-Danlos Syndrome Cause Elevated Ferritin?

No, Ehlers-Danlos syndrome (EDS) does not cause elevated ferritin levels. EDS is a connective tissue disorder affecting collagen synthesis, and there is no established pathophysiologic mechanism linking it to ferritin elevation 1, 2, 3.

Why This Question Arises

The confusion likely stems from the fact that EDS patients often have chronic pain, functional disorders, and may develop secondary inflammatory conditions 1. However, if ferritin is elevated in an EDS patient, you must investigate the actual cause rather than attributing it to the EDS itself.

What Actually Causes Elevated Ferritin

When you encounter elevated ferritin in any patient (including those with EDS), the differential diagnosis includes 4:

Most Common Causes (>90% of cases)

• Chronic inflammation - from any source including chronic pain syndromes 4
• Metabolic syndrome/NAFLD - hepatocellular injury and insulin resistance 4, 5
• Chronic alcohol consumption 4
• Cell necrosis - muscle or liver damage 4
• Malignancy - solid tumors or lymphomas (most frequent cause when ferritin >1000 μg/L) 4, 6

Less Common But Important Causes

• Infections - ferritin rises as an acute phase reactant 4
• Hereditary hemochromatosis - only when transferrin saturation ≥45% 4, 7
• Viral hepatitis (B or C) 4
• Adult-onset Still's disease - extremely high levels (>10,000 μg/L) with glycosylated ferritin <20% 4

The Critical First Step: Check Transferrin Saturation

Never interpret ferritin alone. You must measure fasting transferrin saturation (TS) simultaneously 4, 7, 5:

• If TS ≥45%: Suspect iron overload and proceed to HFE genetic testing for C282Y and H63D mutations 4, 7
• If TS <45%: Iron overload is unlikely; focus on secondary causes (inflammation, liver disease, malignancy, metabolic syndrome) 4, 7

Specific Considerations for EDS Patients

Bleeding Tendency Does Not Cause Hyperferritinemia

• EDS patients have platelet function abnormalities and increased bleeding risk, but this causes iron deficiency (low ferritin), not elevation 8
• 90% of EDS patients with abnormal bleeding have platelet dysfunction 8

Chronic Inflammation as the Bridge

• EDS patients experience chronic pain and functional disorders 1
• If chronic inflammation develops secondarily, ferritin may rise as an acute phase reactant 4
• This represents inflammation-related hyperferritinemia, not an EDS-specific phenomenon 4

Diagnostic Algorithm for Elevated Ferritin in an EDS Patient

1. Order simultaneously: Fasting transferrin saturation and serum ferritin 4, 7

2. Add baseline labs: Complete metabolic panel (ALT, AST), inflammatory markers (CRP, ESR), CBC with differential 4, 7

3. Interpret based on TS 4, 7:

   • TS ≥45%: Order HFE genetic testing → If C282Y homozygote, diagnose hereditary hemochromatosis
   • TS <45%: Evaluate for secondary causes below

4. Investigate secondary causes when TS <45% 4, 6:

   • Screen for malignancy (most common cause when ferritin >1000 μg/L) 6
   • Assess for metabolic syndrome/NAFLD with liver ultrasound 5
   • Evaluate alcohol consumption history 4
   • Check for active infection 4
   • Consider muscle injury (check CK) 4

5. Risk stratification by ferritin level 4, 7:

   • <1000 μg/L: Low risk of organ damage; treat underlying cause
   • 1000-10,000 μg/L: Consider liver biopsy if elevated liver enzymes present 7
   • >10,000 μg/L: Urgent specialist referral for life-threatening conditions (adult-onset Still's disease, hemophagocytic lymphohistiocytosis, malignancy) 4, 7

Critical Pitfalls to Avoid

• Do not attribute elevated ferritin to EDS itself - there is no pathophysiologic connection 1, 2, 3
• Never use ferritin alone without transferrin saturation - ferritin is an acute phase reactant elevated in many conditions independent of iron stores 4, 7, 5
• Do not assume iron overload when TS <45% - over 90% of elevated ferritin cases are NOT due to iron overload 4
• Do not overlook malignancy - it is the most frequent cause when ferritin exceeds 1000 μg/L 6
• Do not delay liver biopsy when ferritin >1000 μg/L with abnormal liver enzymes 7

Management Approach

Treat the underlying condition, not the ferritin number 7:

• If hereditary hemochromatosis confirmed (C282Y homozygote with TS ≥45%): Initiate therapeutic phlebotomy targeting ferritin 50-100 μg/L 7
• If NAFLD/metabolic syndrome: Weight loss and lifestyle modifications 5
• If inflammation: Disease-specific anti-inflammatory therapy 7
• If malignancy: Oncologic treatment 4
• If infection: Antimicrobial therapy 4