What is the diagnosis for iron overload?

Diagnosis of Iron Overload

The diagnosis of iron overload is established by demonstrating elevated transferrin saturation (TS) and serum ferritin levels, followed by genetic testing for HFE mutations (C282Y and H63D) to confirm hereditary hemochromatosis, with liver biopsy or MRI reserved for quantifying hepatic iron content when needed. 1

Initial Screening: Serologic Iron Markers

The diagnostic approach begins with indirect serologic markers of iron stores 1:

• Transferrin saturation (TS) is the primary screening test, calculated by dividing serum iron by total iron-binding capacity 1

  • Cutoff values: >50% for women, >60% for men (sensitivity 0.92, specificity 0.93, positive predictive value 86%) 1
  • Lowering the cutoff to >45% increases sensitivity but reduces specificity 1
  • Fasting samples are advisable for confirmation, though recent data show no significant improvement in detection rates 1

• Serum ferritin should be measured simultaneously with TS to increase diagnostic accuracy 1

  • Elevated ferritin reflects increased hepatic iron content 1
  • Ferritin >1,000 ng/mL predicts significant hepatic fibrosis or cirrhosis in confirmed hemochromatosis 1

Important caveat: Elevated ferritin can occur in inflammatory conditions, chronic liver disease, malignancy, infections, and kidney failure—not just iron overload 2. This is why TS must be elevated concurrently to suggest true iron overload.

Genetic Testing: HFE Mutation Analysis

When both TS and ferritin are elevated, proceed to genetic testing 1:

• Test for three HFE mutations: C282Y, H63D, and S65C 3

  • C282Y homozygosity (C282Y/C282Y) accounts for >90% of hereditary hemochromatosis cases 1
  • C282Y/H63D compound heterozygosity accounts for 3-5% of cases 1
  • All C282Y homozygotes have elevated TS (100% positive predictive accuracy), but only 58-70% develop progressive iron overload 1

• If HFE testing is negative, consider non-HFE hereditary hemochromatosis (10-15% of cases) 1, 3:

  • HJV (hemojuvelin): most common cause of juvenile hemochromatosis 1, 3
  • HAMP (hepcidin): causes juvenile hemochromatosis but much less common 1, 3
  • TFR2 (transferrin receptor-2): causes adult-onset disease similar to HFE-related hemochromatosis 1, 3
  • SLC40A1 (ferroportin): causes ferroportin disease with autosomal dominant inheritance 1, 3

Quantifying Iron Overload: Liver Assessment

Liver biopsy or MRI is indicated in specific circumstances 1, 4:

• Liver biopsy is recommended for 1:

  • Patients >40 years old with serum ferritin >1,000 ng/mL (to assess for cirrhosis)
  • Patients with elevated liver enzymes or hepatomegaly
  • When iron markers are equivocal despite genetic testing
  • Hepatic iron concentration (HIC) provides quantitative assessment of iron stores

• MRI has emerged as the reference standard for detecting and quantifying hepatic iron deposition 4:

  • Non-invasive alternative to biopsy
  • Cardiac MRI T2* can assess cardiac iron deposition (important in transfusional iron overload) 5, 4

Target Populations for Evaluation

High-risk groups requiring screening 1:

Symptomatic Patients

• Unexplained liver disease with abnormal iron markers 1
• Type 2 diabetes with hepatomegaly, elevated liver enzymes, or atypical cardiac disease 1
• Early-onset arthropathy (especially metacarpophalangeal joints), cardiac disease, or sexual dysfunction 1
• Weakness, fatigue, abdominal pain, arthralgias, loss of libido, impotence, or heart failure symptoms 1

Asymptomatic Patients (Priority Groups)

• First-degree relatives of confirmed hemochromatosis cases 1
• Individuals with abnormal iron markers on routine testing 1
• Unexplained elevation of liver enzymes or hepatomegaly 1

Secondary Iron Overload

If genetic testing is negative, evaluate for secondary causes 1, 2:

• Iron-loading anemias: thalassemia major, sideroblastic anemia, chronic hemolytic anemia, myelodysplastic syndrome 1, 2
• Transfusional iron overload: multiple red blood cell transfusions, long-term hemodialysis 1, 6
• Chronic liver disease: hepatitis B/C, alcoholic liver disease, nonalcoholic fatty liver disease, porphyria cutanea tarda 1, 2
• Iatrogenic: parenteral iron administration (iron-dextran injections) 1

Critical distinction: Oral iron ingestion does not cause iron overload except in genetically predisposed individuals 1.

Diagnostic Algorithm Summary

1. Measure TS and ferritin in suspected cases or high-risk populations 1
2. If both elevated: Proceed to HFE genetic testing (C282Y, H63D, S65C) 1, 3
3. If C282Y homozygous or C282Y/H63D compound heterozygous: Diagnosis confirmed 1
   • Assess need for liver biopsy based on age, ferritin level, and liver enzyme status 1
4. If HFE negative: Consider expanded genetic panel (HJV, HAMP, TFR2, SLC40A1) or evaluate for secondary causes 3, 2
5. Use MRI or liver biopsy to quantify iron burden when clinically indicated 1, 4