What are the reasons for and management of elevated percent saturation (percent sat) iron readings?

Causes and Management of Elevated Transferrin Saturation (Percent Sat) Iron

Elevated transferrin saturation (>45% in females or >50% in males) primarily indicates hemochromatosis or iron overload, requiring genetic testing for HFE mutations and phlebotomy treatment to prevent organ damage and mortality. 1

Common Causes of Elevated Transferrin Saturation

Primary Causes

• Hereditary Hemochromatosis
  • Most commonly associated with homozygosity for p.Cys282Tyr mutation in the HFE gene 1
  • Compound heterozygotes with p.H63D and p.C282Y mutations may also develop iron overload 1

Secondary Causes

• Transfusional Iron Overload
  • Particularly with TSAT >80% 1
• Liver Disease
  • Nonalcoholic fatty liver disease (NAFLD) 2
  • Chronic hepatitis C infection 2
  • Alcohol-related liver disease 2
• Hematologic Disorders
  • Thalassemia syndromes
  • Myelodysplastic syndrome
  • Myelofibrosis
  • Sideroblastic anemias 3
• Iatrogenic Causes
  • Recent intravenous iron administration (can falsely elevate results for up to 4 weeks) 4
  • Excessive oral iron supplementation

Diagnostic Approach

1. Confirm Elevated TSAT

   • Females: TSAT >45% with ferritin >200 μg/L suggests hemochromatosis 1
   • Males: TSAT >50% with ferritin >300 μg/L suggests hemochromatosis 1
   • Severe iron overload: TSAT >80% 1

2. Evaluate for Discordant Iron Parameters

   • If TSAT is elevated but ferritin is normal/low: Consider physiological fluctuations, recent IV iron, or early hemochromatosis 5
   • If ferritin is elevated but TSAT is low/normal: Consider inflammatory conditions, which can mask iron overload 1

3. Genetic Testing

   • Test for HFE gene mutations (p.Cys282Tyr homozygosity or compound heterozygosity) 1
   • Positive genetic test with elevated iron parameters confirms hereditary hemochromatosis

4. Assess Organ Involvement

   • MRI for hepatic iron quantification
   • Evaluate liver fibrosis
   • Screen for diabetes, arthropathy, and cardiac involvement 1

Management Strategies

For Hereditary Hemochromatosis

1. Phlebotomy Therapy

   • Induction Phase: Regular phlebotomies until ferritin <50 μg/L
   • Maintenance Phase: Periodic phlebotomies to maintain ferritin <100 μg/L 1

2. Monitoring During Treatment

   • Check hemoglobin and iron parameters every 4-8 weeks initially
   • Continue treatment for approximately 3 months after normalization
   • Long-term monitoring every 3-6 months 1

For Secondary Iron Overload

1. Treat Underlying Cause

   • Address liver disease, hematologic disorders, or other primary conditions

2. Iron Chelation Therapy (if phlebotomy contraindicated)

   • Deferasirox is an option for transfusional iron overload 6
   • Starting dose: 14 mg/kg/day (oral tablets)
   • Dose adjustments based on response and renal function 6
   • Contraindicated in patients with eGFR <40 mL/min/1.73 m² 6

3. Dietary Modifications

   • Limit alcohol consumption (increases risk of fibrosis and hepatocellular carcinoma) 1
   • Avoid vitamin C supplements with meals (enhances iron absorption)
   • Avoid raw shellfish (risk of Vibrio infection in iron-overloaded patients)

Special Considerations

Laboratory Monitoring

• Do not evaluate iron parameters within 4 weeks of IV iron administration (can interfere with assay results) 4
• In patients with inflammatory conditions, consider soluble transferrin receptor (sTfR) testing, which is not affected by inflammation 4

Common Clinical Manifestations

• Arthralgia (42% in hemochromatosis vs. 16% in other conditions) 2
• Decreased libido (11% vs. 4%) 2
• Fatigue (44% vs. 33%) 2
• Diabetes and hypothyroidism may be more common 2

Pitfalls to Avoid

• Failing to test for hemochromatosis in patients with unexplained elevated liver enzymes
• Attributing elevated ferritin solely to inflammation without checking TSAT
• Overlooking the need for genetic testing in patients with elevated TSAT
• Delaying treatment in confirmed cases, which can lead to irreversible organ damage 1

Early diagnosis and treatment of iron overload through appropriate interventions can prevent serious complications including cirrhosis, hepatocellular carcinoma, diabetes, and arthropathy, significantly improving mortality and quality of life outcomes 1.