What causes high iron levels and how are they managed?

Causes and Management of High Iron Levels

Therapeutic phlebotomy is the first-line treatment for high iron levels, with a goal to reduce ferritin to 50-100 μg/L through weekly removal of 500 mL of blood. 1

Causes of High Iron Levels

Hereditary Causes

• Hereditary Hemochromatosis (HH)
  • HFE-related: C282Y homozygosity, C282Y/H63D compound heterozygosity 2
  • Non-HFE related: Other gene mutations 2
  • Juvenile hemochromatosis 2
  • Autosomal dominant hemochromatosis 2
• Other Rare Hereditary Disorders
  • Transferrin receptor 2 mutations (hemochromatosis type 3) 3
  • Ferroportin mutations (hemochromatosis type 4) 3
  • L-ferritin mutations causing neurodegeneration 3

Secondary Causes

• Iron-Loading Anemias
  • Thalassemia major 2
  • Sideroblastic anemia 2
  • Chronic hemolytic anemias 2
• Transfusional Iron Overload
  • Multiple blood transfusions for chronic anemia 4
  • Myelodysplastic syndromes requiring transfusions 2
• Chronic Liver Diseases
  • Hepatitis B and C 2
  • Alcoholic liver disease 2
  • Fatty liver disease 2
  • Porphyria cutanea tarda 2
• Other Causes
  • Dietary iron overload 2
  • African iron overload 2
  • Aceruloplasminemia 2
  • Congenital atransferrinemia 2

Diagnosis of Iron Overload

1. Laboratory Testing

   • Serum ferritin (elevated >1000 ng/mL suggests significant iron overload) 1
   • Transferrin saturation (>50% for women, >60% for men) 2
   • Fasting values are preferred to avoid circadian variations 2

2. Genetic Testing

   • HFE gene testing for C282Y and H63D mutations 5

3. Imaging and Tissue Assessment

   • MRI for quantitative assessment of liver iron content 5
   • Liver biopsy (especially if liver disease is suspected) 5

Management of Iron Overload

Therapeutic Phlebotomy (First-Line Treatment)

• For Hereditary Hemochromatosis and Other Primary Iron Overload Conditions
  • Remove 500 mL of blood weekly or biweekly 2, 1
  • Check hematocrit before each procedure; avoid >20% drop from previous level 2, 1
  • Monitor serum ferritin every 10-12 phlebotomies 2
  • Initial goal: Reduce ferritin to below 50 ng/mL 2
  • Maintenance: Continue phlebotomies at intervals to maintain ferritin between 25-50 ng/mL 2

Iron Chelation Therapy

• For Secondary Iron Overload or When Phlebotomy is Contraindicated
  • Deferoxamine: 20-40 mg/kg/day 2
  • Deferasirox: For transfusional iron overload 6
  • Consider for patients with ferritin >1000 ng/mL who cannot tolerate phlebotomy 1

Special Populations

• Myelodysplastic Syndromes

  • Consider chelation for transfusion-dependent patients requiring ≥2 units/month for >1 year 2
  • Target patients with ferritin >1000 ng/mL and low-risk MDS 2
  • Continue chelation as long as transfusions are needed 2

• Post-Transplant Patients

  • Phlebotomy is preferred in patients with favorable prognosis >1 year after stem cell transplant 2

Monitoring and Follow-up

• Regular monitoring of ferritin levels, liver function tests, and complete blood count 1
• Surveillance for hepatocellular carcinoma in patients with cirrhosis 1
• Monitor cardiac and endocrine function in severe iron overload 1

Lifestyle Modifications

• Avoid vitamin C supplements (>500 mg/day) 2, 1
• Limit iron-rich foods and alcohol intake 1
• Avoid raw shellfish due to infection risk in iron-overloaded patients 1

Clinical Outcomes and Prognosis

Early diagnosis and treatment of iron overload significantly improves survival and prevents complications 2. Untreated iron overload can lead to:

• Liver cirrhosis and hepatocellular carcinoma (30% of deaths in HH) 2
• Cardiac dysfunction and arrhythmias 2, 1
• Diabetes mellitus 2
• Arthropathy 2
• Endocrine dysfunction 2

Treatment initiated before the development of cirrhosis or diabetes can normalize life expectancy 2.