In an adult with normal total iron‑binding capacity, elevated serum iron, and high transferrin‑saturation, what is the most likely diagnosis and what are the appropriate evaluation and management steps?

Hereditary Hemochromatosis: Diagnosis and Management

In an adult with normal TIBC, elevated serum iron, and high transferrin saturation, the most likely diagnosis is hereditary hemochromatosis (HFE-related), and you should immediately order HFE genetic testing for C282Y and H63D mutations. 1

Diagnostic Interpretation

The combination of elevated transferrin saturation (>45% in women, >50% in men) with normal TIBC is the hallmark biochemical pattern of hereditary hemochromatosis, distinguishing it from secondary iron overload conditions. 1, 2

Key Laboratory Features in Hemochromatosis:

• Transferrin saturation >45% (women) or >50% (men) indicates excessive iron loading of transferrin binding sites 1
• Normal TIBC reflects normal transferrin production, ruling out inflammatory conditions that suppress transferrin synthesis 2
• Elevated serum iron results from increased intestinal iron absorption due to hepcidin deficiency 1
• Elevated serum ferritin (typically >200 μg/L in women, >300 μg/L in men) reflects increased total body iron stores 1

This pattern contrasts sharply with iron deficiency (low iron, high TIBC, low saturation) and anemia of chronic disease (low iron, low TIBC, low saturation). 1, 3

Immediate Diagnostic Workup

Step 1: Confirm Iron Overload Pattern

• Repeat fasting transferrin saturation and serum ferritin to confirm persistently elevated values, as diurnal variation and recent meals can transiently elevate serum iron 1, 4
• Obtain complete blood count to assess for polycythemia or other hematologic abnormalities 1
• Measure inflammatory markers (CRP, ESR) to exclude inflammation artificially elevating ferritin 1

Step 2: HFE Genetic Testing

Order HFE genotyping for C282Y and H63D mutations in all individuals of European ancestry with transferrin saturation >45% (women) or >50% (men) and ferritin >200 μg/L (women) or >300 μg/L (men). 1

• C282Y homozygosity accounts for 80–90% of clinical hemochromatosis cases 1, 5
• C282Y/H63D compound heterozygosity causes milder iron overload, typically requiring additional risk factors (alcohol, fatty liver) to manifest clinically 1
• H63D homozygosity rarely causes significant iron overload alone 1

Step 3: Quantify Iron Burden

If genetic testing confirms hemochromatosis or if clinical suspicion remains high despite negative HFE testing:

• Liver MRI with T2 or R2 quantification** provides non-invasive measurement of hepatic iron concentration 1
• Liver biopsy is reserved for cases with suspected advanced fibrosis, elevated liver enzymes, or when non-HFE hemochromatosis is suspected 1
• Calculate hepatic iron index (hepatic iron concentration [μmol/g] ÷ age [years]) if biopsy is performed; values >1.9 suggest genetic hemochromatosis 1

Evaluation for End-Organ Damage

Hepatic Assessment

• Liver enzymes (AST, ALT, alkaline phosphatase) to detect hepatocellular injury 1
• Non-invasive fibrosis markers (FIB-4, APRI) using lower thresholds than in other liver diseases (FIB-4 >1.3 warrants further evaluation) 1
• Transient elastography if available, though validation in hemochromatosis is limited 1
• Liver biopsy if ferritin >1000 μg/L, elevated liver enzymes, or hepatomegaly to stage fibrosis and assess cirrhosis risk 1

Cardiac Evaluation

• Electrocardiogram to detect conduction abnormalities 1
• Echocardiography if severe iron overload (ferritin >1000 μg/L) or cardiac symptoms 1
• Cardiac MRI with T2 quantification* for myocardial iron assessment in severe cases or juvenile hemochromatosis 1

Endocrine and Metabolic Screening

• Fasting glucose and HbA1c to screen for diabetes mellitus 1
• Testosterone, LH, FSH in men with hypogonadism symptoms 1
• Thyroid function tests if clinically indicated 1

Musculoskeletal Assessment

• Plain radiographs of symptomatic joints (especially 2nd/3rd metacarpophalangeal joints, wrists, hips, knees) to detect characteristic arthropathy with hook-like osteophytes and chondrocalcinosis 1
• Joint disease occurs in 86.5% of hemochromatosis patients and does not improve with phlebotomy 1

Differential Diagnosis When HFE Testing is Negative

If C282Y homozygosity or C282Y/H63D compound heterozygosity is absent, consider secondary causes of iron overload: 1, 5, 2

Hematologic Disorders

• Thalassemia syndromes (check hemoglobin electrophoresis, MCV) 5
• Myelodysplastic syndrome (check CBC with differential, peripheral smear) 1, 5
• Sideroblastic anemia (bone marrow examination) 5
• Chronic hemolytic anemias (sickle cell disease, pyruvate kinase deficiency) 5

Non-HFE Genetic Hemochromatosis

Order gene panel sequencing (HJV, HAMP, TFR2, SLC40A1, CP) if phenotype suggests genetic hemochromatosis but HFE testing is negative. 1

• Juvenile hemochromatosis (HJV, HAMP mutations) presents before age 30 with severe cardiac and endocrine involvement 1
• Ferroportin disease (SLC40A1 mutations) shows elevated ferritin with normal or low transferrin saturation 1

Acquired Iron Overload

• Chronic liver disease (viral hepatitis, alcohol, NAFLD) with dysmetabolic iron overload 5, 2
• Iatrogenic iron overload from chronic transfusions or parenteral iron therapy 1, 5
• Porphyria cutanea tarda (check urine porphyrins) 5

Treatment Algorithm

Phlebotomy Therapy (First-Line)

Initiate therapeutic phlebotomy immediately in confirmed hemochromatosis with ferritin >300 μg/L (men) or >200 μg/L (women) and transferrin saturation >45%. 1

Induction Phase:

• Remove 500 mL blood weekly (or 7 mL/kg in smaller patients) until ferritin reaches 50–100 μg/L 1
• Monitor ferritin every 10–12 phlebotomies during induction 1
• Each 500 mL phlebotomy removes approximately 200–250 mg iron 1

Maintenance Phase:

• Continue phlebotomy every 2–4 months to maintain ferritin 50–100 μg/L and transferrin saturation <50% 1
• Monitor ferritin every 6–12 months once stable 1

Iron Chelation Therapy

Reserve chelation for patients unable to tolerate phlebotomy (severe anemia, cardiac disease, poor venous access). 1

• Deferasirox is the preferred oral chelator 1
• Monitor liver and renal function during chelation therapy 1

Lifestyle Modifications

• Avoid or strictly limit alcohol consumption, as it accelerates liver damage in iron overload 1
• Avoid raw or undercooked shellfish due to risk of fatal Vibrio vulnificus septicemia in iron-overloaded patients (>50% mortality) 1
• Avoid iron supplements and high-dose vitamin C (>500 mg/day), which increases iron absorption 1
• Moderate dietary iron restriction is unnecessary once phlebotomy is established 1

Family Screening

Test all first-degree relatives of C282Y homozygotes with HFE genotyping after informed consent. 1

• If relatives are C282Y homozygotes, measure ferritin and transferrin saturation annually starting at age 18 1
• If relatives are C282Y heterozygotes or wild-type, no further screening is needed unless iron studies are abnormal 1

Common Pitfalls to Avoid

• Do not dismiss elevated transferrin saturation if ferritin is normal or mildly elevated—transferrin saturation rises years before ferritin in early hemochromatosis 1, 2
• Do not attribute hyperferritinemia to inflammation without checking transferrin saturation—hemochromatosis can coexist with inflammatory conditions 1, 2
• Do not delay phlebotomy pending liver biopsy in patients with ferritin <1000 μg/L and normal liver enzymes—biopsy is unnecessary for diagnosis or treatment initiation 1
• Do not assume H63D homozygosity or C282Y/H63D compound heterozygosity alone explains significant iron overload—search for additional causes (alcohol, NAFLD, other genetic mutations) 1
• Do not stop monitoring after initial treatment—lifelong surveillance is required as iron reaccumulates 1