How do you interpret and manage abnormal iron studies, including iron deficiency and overload?

Iron Studies Interpretation and Management

Interpret iron studies systematically using transferrin saturation (TSAT) and ferritin as primary markers, with TSAT >45% plus ferritin >200 μg/L (women) or >300 μg/L (men) indicating iron overload requiring genetic testing, while ferritin <45 μg/L defines iron deficiency warranting investigation for underlying causes. 1

Iron Deficiency: Diagnostic Approach

Initial Laboratory Interpretation

• Serum ferritin is the single most useful marker for iron deficiency, with <15 μg/L being highly specific (specificity 0.99) for absent iron stores 1
• Use ferritin <45 μg/L as the practical threshold for iron deficiency, providing optimal sensitivity-specificity balance (specificity 0.92), particularly important when inflammation may falsely elevate ferritin 1
• Ferritin >150 μg/L essentially excludes absolute iron deficiency, even with concurrent inflammation 1
• Mean cell hemoglobin (MCH) may be more reliable than MCV for detecting iron deficiency, as it's less affected by storage conditions and detects both absolute and functional iron deficiency 1

Defining Iron Deficiency Anemia

Iron deficiency anemia requires BOTH: 1

• Hemoglobin <13 g/dL (men) or <12 g/dL (non-pregnant women)
• Ferritin <45 ng/mL

Critical caveat: Ferritin is an acute phase reactant—interpret cautiously in chronic kidney disease, inflammatory states, or chronic disease where apparently "normal" levels may mask true deficiency 1

Gastrointestinal Evaluation Algorithm

For asymptomatic patients with confirmed iron deficiency anemia: 1

1. First-line non-invasive testing:

   • H. pylori testing (non-invasive)
   • Celiac disease serology (found in 3-5% of IDA cases) 1

2. If negative, proceed to bidirectional endoscopy:

   • Strong recommendation for men and postmenopausal women (moderate quality evidence) 1
   • Conditional recommendation for premenopausal women who value detecting rare neoplasia over avoiding endoscopy risks 1
   • Younger premenopausal women may reasonably choose empiric iron supplementation initially 1

3. Reserve biopsies for:

   • Celiac disease: only if positive serology or endoscopic abnormality 1
   • H. pylori: only if endoscopic abnormality with negative non-invasive testing 1

4. If bidirectional endoscopy unrevealing:

   • Trial iron supplementation
   • If anemia persists or recurs: video capsule endoscopy for small bowel evaluation 1
   • Consider capsule endoscopy earlier in patients requiring antiplatelet/anticoagulation 1

Response to Iron Therapy as Diagnostic Tool

A hemoglobin rise ≥10 g/L within 2 weeks is highly suggestive of absolute iron deficiency, even with equivocal iron studies 1

Iron Overload: Diagnostic Approach

Initial Screening Parameters

Suspect iron overload when: 1

• Transferrin saturation >45% AND
• Ferritin >200 μg/L (females) or >300 μg/L (males)

Genetic Testing Strategy

Proceed directly to HFE genotyping for patients of European origin with elevated TSAT and ferritin 1

For non-European patients, consider direct sequencing of HFE and non-HFE genes (HJV, TFR2, CP, SLC40A1) without preliminary HFE genotyping, as C282Y prevalence is very low 1

Risk Stratification by Genotype

C282Y homozygotes <40 years old without clinical liver disease or ferritin <1,000 μg/L: 1

• May proceed directly to therapeutic phlebotomy without liver biopsy

C282Y homozygotes ≥40 years old OR ferritin >1,000 μg/L: 1

• Liver biopsy recommended to assess for cirrhosis
• Consider non-invasive fibrosis assessment (transient elastography with cutoff <6.4 kPa rules out advanced fibrosis) 1

Compound heterozygotes (C282Y/H63D) or H63D homozygotes: 1

• Require individualized assessment
• Only treat with phlebotomy if confirmed iron overload by MRI or biopsy
• Investigate for additional environmental risk factors (alcohol, metabolic syndrome)

Cardiac Assessment in Iron Overload

Cardiac MRI with T2/R2 is essential for:** 1

• All patients with juvenile hemochromatosis (HJV, HAMP mutations) at diagnosis—cardiac involvement occurs in majority, with severe heart failure possible before age 30 1
• Patients with severe iron overload (ferritin levels suggesting rapid accumulation) plus any cardiac symptoms or ECG abnormalities 1
• HFE-hemochromatosis patients with signs of heart disease (arrhythmias, conduction abnormalities, heart failure symptoms) 1

T2 risk stratification:* 1

• T2* >20 ms (green zone): Low imminent heart failure risk
• T2* 10-20 ms (yellow zone): Intermediate risk, probable cardiac iron deposition
• T2* <10 ms (red zone): High risk—requires immediate intensive chelation therapy

Baseline cardiac evaluation should include: 1

• ECG and Holter monitoring (detect conduction disease, arrhythmias)
• Transthoracic echocardiography (assess diastolic dysfunction, which precedes systolic dysfunction)
• Cardiac MRI R2* for myocardial iron quantification

Hepatic Assessment

Non-invasive fibrosis assessment: 1

• Transient elastography <6.4 kPa effectively rules out advanced fibrosis
• FIB-4 and APRI scores have limited validation in hemochromatosis (lower thresholds than other liver diseases)

Liver biopsy indications: 1

• Ferritin >1,000 μg/L with inability to confirm/exclude cirrhosis non-invasively
• Compound heterozygotes with iron overload
• Suspected additional liver disease

Hepatocellular Carcinoma Surveillance

Every 6 months surveillance required for: 1

• Confirmed cirrhosis (METAVIR F4/Ishak stage 6), regardless of iron depletion status
• Consider for advanced fibrosis (METAVIR F3/Ishak stages 4-5)
• Continue even if fibrosis regresses to F2 or less after treatment (individualize interval)

Key Pitfalls to Avoid

• Don't rely on ferritin alone in inflammatory conditions—use 45 μg/L threshold and consider transferrin saturation, or trial iron therapy with response assessment 1
• Don't skip celiac screening—present in 3-5% of IDA cases and easily missed 1
• Don't assume menstruation explains IDA in premenopausal women without investigation if ferritin <45 μg/L, especially with GI symptoms 1
• Don't delay cardiac assessment in juvenile hemochromatosis—cardiac iron deposition can cause sudden death even without overt heart failure 1
• Don't use H63D testing for hemochromatosis diagnosis—it lacks clinical utility and creates confusion 1
• Don't assume normal iron studies exclude iron deficiency in chronic disease—hepcidin elevation causes functional iron deficiency with "normal" ferritin 2, 3