What causes elevated serum iron levels?

Causes of High Serum Iron

Elevated serum iron levels are primarily caused by hereditary hemochromatosis, secondary iron overload conditions, and various medical disorders affecting iron metabolism.

Primary Causes (Hereditary)

Hereditary Hemochromatosis (HH)

• HFE-related hemochromatosis (most common form) 1

  • C282Y homozygosity (accounts for ~90% of cases) 2
  • C282Y/H63D compound heterozygosity
  • Other HFE mutations

• Non-HFE related hemochromatosis 1

  • Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin genes)
  • Transferrin receptor-2 (TfR2) mutations
  • Ferroportin (SLC40A1) mutations
  • Hepcidin (HAMP) mutations

Secondary Causes

Iron-Loading Anemias 1

• Thalassemia major
• Sideroblastic anemia
• Chronic hemolytic anemias
• Aplastic anemia
• Pyruvate kinase deficiency 3
• Pyridoxine-responsive anemia

Parenteral Iron Overload 1

• Red blood cell transfusions
• Iron-dextran injections
• Long-term hemodialysis

Chronic Liver Disease 1

• Porphyria cutanea tarda
• Hepatitis C
• Hepatitis B
• Alcoholic liver disease
• Nonalcoholic fatty liver disease
• Post-portocaval shunt
• Dysmetabolic iron overload syndrome

Dietary and Environmental Factors

• Excessive dietary iron intake
• African iron overload (traditional beer fermented in steel drums) 1
• High-dose vitamin C supplementation (in predisposed individuals) 4

Miscellaneous Causes 1

• Neonatal iron overload
• Aceruloplasminemia
• Congenital atransferrinemia

Pathophysiology

The pathophysiology of iron overload involves several mechanisms:

1. Increased intestinal iron absorption - Primary mechanism in hereditary hemochromatosis 1
2. Decreased hepcidin expression - Hepcidin is the key iron-regulatory hormone; deficiency leads to increased iron absorption 1
3. Altered function of HFE protein - Affects iron sensing and regulation 1
4. Parenteral administration - Bypasses normal regulatory mechanisms 1

Clinical Presentation and Diagnostic Indicators

Laboratory Findings

• Elevated transferrin saturation (>45% in women, >50% in men) 2
• Elevated serum ferritin (>200 μg/L in women, >300 μg/L in men) 2
• Ferritin levels >1000 μg/L suggest high risk of cirrhosis (20-45%) 2

Clinical Manifestations

• Often asymptomatic in early stages
• Fatigue, weakness, lethargy
• Abdominal pain (hepatomegaly)
• Arthralgias (especially metacarpophalangeal joints)
• Skin pigmentation
• Diabetes mellitus
• Cardiac abnormalities (arrhythmias, heart failure)
• Sexual dysfunction 1

Diagnostic Approach

1. Initial testing: Serum iron, transferrin saturation, serum ferritin 2
2. Genetic testing: HFE gene mutations (C282Y, H63D) for suspected hereditary hemochromatosis 2
3. Confirmatory testing: Liver biopsy or MRI for iron quantification when needed 2

Clinical Pitfalls and Caveats

• False positives: Serum ferritin can be elevated in inflammatory conditions without true iron overload 5
• Early disease: In precirrhotic stages of primary hemochromatosis, serum ferritin may remain normal despite iron overload 5
• Alcohol consumption: Downregulates hepcidin transcription via oxidative stress, worsening iron accumulation 1
• Infection risk: Patients with iron overload are at increased risk for severe Vibrio vulnificus infections 1
• Vitamin C supplementation: May enhance iron absorption in patients with iron overload 4

Management Considerations

• Early diagnosis is crucial to prevent organ damage and dysfunction 1
• Therapeutic phlebotomy is the mainstay of treatment for true iron overload 2
• Alcohol avoidance or limitation is recommended for patients with iron overload 1
• Regular monitoring of iron parameters is essential for patients with confirmed iron overload 2

Understanding the cause of elevated serum iron is essential for appropriate management and prevention of complications such as cirrhosis, diabetes, and cardiomyopathy.