What is the diagnostic approach for a middle-aged patient of Northern European descent with a family history of hemochromatosis (iron overload disorder) or liver disease, suspected of having hemochromatosis?

Diagnostic Approach for Hemochromatosis

Initial Laboratory Testing

Begin with simultaneous measurement of transferrin saturation (TS) and serum ferritin as the essential first-line tests for suspected hemochromatosis. 1, 2

• Calculate transferrin saturation as: (serum iron ÷ total iron-binding capacity) × 100 2
• Diagnostic thresholds that trigger further evaluation:
  • Transferrin saturation ≥45% (most sensitive early marker) 1, 2
  • Serum ferritin >300 μg/L in men or >200 μg/L in women 1, 2
• Obtain complete blood count with reticulocytes to exclude anemia and red cell disorders 1

Critical pitfall: Ferritin can be falsely elevated by inflammation, chronic liver disease, malignancy, non-alcoholic fatty liver disease, and metabolic syndrome—these must be excluded before attributing elevated ferritin to hemochromatosis. 1, 2

Genetic Testing Protocol

If either TS ≥45% OR ferritin exceeds the thresholds above, proceed immediately to HFE gene mutation analysis for C282Y and H63D mutations. 1, 2

• For patients of Northern European descent, test for C282Y first, as this mutation accounts for 85-90% of clinically affected patients 1, 2
• C282Y homozygosity (C282Y/C282Y) confirms HFE-related hemochromatosis 2
• Include H63D testing, as compound heterozygosity (C282Y/H63D) can occasionally cause iron overload 1, 2

For patients of non-European origin with elevated TS and ferritin, consider direct sequencing of a broader gene panel (HFE, HJV, TFR2, CP, SLC40A1) without initial HFE genotyping, as the pre-test probability for C282Y is very low. 1

Assessment for Advanced Disease and Complications

Evaluate for cirrhosis and end-organ damage after genetic confirmation using the following algorithm: 1, 2

Liver Assessment

• If ferritin >1,000 μg/L with elevated ALT/AST AND platelet count <200: This predicts cirrhosis in ~80% of C282Y homozygotes—strongly consider liver biopsy 1, 2
• If ferritin <1,000 μg/L: This accurately excludes cirrhosis regardless of genotype 2
• Additional indications for liver biopsy: hepatomegaly on exam, age >40 years in C282Y homozygotes 2
• Non-invasive fibrosis scores (APRI, FIB-4) can be used, but thresholds are lower than in other liver diseases 1

Cardiac Evaluation

• Patients with severe iron overload (ferritin typically >1,000 μg/L) should undergo ECG and echocardiography to screen for arrhythmias and cardiac dysfunction 1
• If signs or symptoms of heart disease present (conduction abnormalities, contractile dysfunction), perform cardiac MRI for myocardial iron quantification without delaying treatment 1
• All patients with juvenile hemochromatosis require cardiac MRI with myocardial iron quantification 1

Musculoskeletal Assessment

• Evaluate for arthropathy, particularly in 2nd/3rd metacarpophalangeal joints, ankles, hips, and wrists 1
• Obtain radiographs if symptomatic: look for joint space narrowing, osteophytes, subchondral cysts, and chondrocalcinosis (present 50% of the time) 1
• Important caveat: Joint disease does not respond uniformly to phlebotomy and requires specific treatment 1

Endocrine and Other Screening

• Screen for diabetes mellitus (pancreatic iron deposition) 3
• Assess for hypogonadism and pituitary dysfunction 3
• Evaluate for skin pigmentation 3

Family Screening Protocol

All first-degree relatives of confirmed hemochromatosis patients should undergo both HFE genetic testing AND simultaneous phenotypic screening (TS and ferritin). 2, 4

• Siblings have the highest yield: 33% show C282Y homozygosity compared to 23% of all first-degree relatives 4
• Genetic counseling should be provided before testing, discussing treatment efficacy, costs, implications for insurability/employment, and psychological impact 2

Imaging for Iron Quantification

MRI should be used to quantify hepatic iron concentration when: 1

• The cause of hyperferritinemia is unclear despite biochemical testing
• Biochemical iron overload is present but genetic testing is negative or inconclusive
• Positive liver iron staining requires quantification

Population-Based Screening

Routine population-wide screening is NOT recommended due to low penetrance and uncertain benefit in asymptomatic genotype-positive individuals. 1, 4

Targeted case-finding IS appropriate for: 1, 4

• Individuals with suggestive symptoms (fatigue, arthralgia, hepatomegaly, diabetes, cardiomyopathy, hypogonadism)
• Abnormal liver function tests of unclear etiology
• Family history of hemochromatosis
• One-time screening of asymptomatic non-Hispanic white men (highest yield population)

Key Diagnostic Pitfalls to Avoid

• Never rely on a single test—always measure TS and ferritin simultaneously, as combined interpretation provides optimal diagnostic accuracy 2
• Normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or compound heterozygotes—do not dismiss this pattern 2
• TS has biological variability—repeat abnormal iron studies to confirm before proceeding to genetic testing 2
• Genotype alone is insufficient—only 50% of C282Y homozygotes develop end-organ damage in population studies, so phenotypic assessment is essential 4