Evaluation and Treatment of Suspected Hereditary Hemochromatosis
Initial Diagnostic Testing
Measure transferrin saturation and serum ferritin simultaneously as your first-line tests—never rely on a single marker. 1, 2
- Transferrin saturation (TS) ≥45% is the most sensitive early screening threshold and the primary trigger for further evaluation 1, 2
- Serum ferritin thresholds: >300 μg/L in men or >200 μg/L in women warrant additional workup 1, 2
- Calculate TS as: (serum iron ÷ total iron-binding capacity) × 100 1
Critical Pitfall: Exclude Secondary Causes First
Before attributing elevated iron studies to hemochromatosis, rule out 1, 2:
- Chronic alcohol consumption
- Non-alcoholic fatty liver disease and metabolic syndrome
- Inflammatory conditions (ferritin is an acute-phase reactant)
- Malignancy and cell necrosis
- Active liver disease from other causes
Ferritin can be falsely elevated in inflammation, making TS the more specific marker in these contexts. 1
Genetic Testing Algorithm
If either TS ≥45% OR ferritin exceeds sex-specific thresholds, immediately order HFE mutation analysis for C282Y and H63D variants. 1, 2
Pre-Test Counseling Requirements
Before ordering genetic testing, discuss 1:
- Efficacy of phlebotomy treatment
- Costs of testing and lifelong monitoring
- Insurance and employment implications
- Psychological impact of genetic disease labeling
- Family screening obligations
- Possibility of uncertain or variant genotypes
Interpretation of HFE Results
- C282Y homozygosity (C282Y/C282Y) confirms HFE-related hemochromatosis and accounts for 85–90% of clinically affected patients 1, 2
- Compound heterozygotes (C282Y/H63D) have lower penetrance and require individualized assessment based on iron parameters rather than genotype alone 1
- H63D homozygotes with confirmed iron overload need investigation for other contributing causes 1
Assessment for Advanced Liver Disease
Liver biopsy is indicated when ANY of the following are present in confirmed cases: 1, 2
| Criterion | Threshold | Rationale |
|---|---|---|
| Serum ferritin | >1,000 μg/L | Predicts cirrhosis in 80% when combined with elevated enzymes and low platelets [1] |
| Liver enzymes | Elevated ALT/AST | Suggests hepatocellular injury [1] |
| Platelet count | <200 × 10⁹/L | Marker of portal hypertension [1] |
| Age | >40 years in C282Y homozygotes | Higher risk of advanced fibrosis [1] |
| Physical exam | Hepatomegaly | Clinical evidence of liver involvement [1] |
Ferritin <1,000 μg/L accurately excludes cirrhosis regardless of genotype. 1
Non-Invasive Alternative
MRI can quantify hepatic iron concentration non-invasively when diagnosis is unclear or to assess extrahepatic organ involvement 1
Treatment: Therapeutic Phlebotomy
Phlebotomy is the mainstay of treatment for confirmed hemochromatosis with iron overload. 2, 3
Standard Protocol 1:
- Remove one unit (≈500 mL) of blood weekly or biweekly
- Monitor hemoglobin/hematocrit before each session
- Check serum ferritin every 10–12 phlebotomies
- Target ferritin: 50–100 μg/L
Monitoring During Treatment 2:
- Serial ferritin and transferrin saturation measurements guide frequency
- Watch for iron avidity (persistently elevated TS despite treatment)—may mimic undertreatment 4
Dietary and Lifestyle Modifications 1:
- Avoid vitamin C supplements (accelerates iron mobilization and toxicity)
- Avoid raw seafood (risk of Vibrio vulnificus infection in iron-overloaded patients)
- Alcohol avoidance is prudent
- General dietary iron restriction is unnecessary 4
Family Screening Protocol
All first-degree relatives of confirmed cases require simultaneous HFE genetic testing AND phenotypic screening (TS + ferritin). 1, 2
- Siblings have the highest yield: 33% show C282Y homozygosity 2
- Penetrance is higher in family members than general population 2
- Test children of a proband after age 18; consider testing the other parent 2
Clinical Presentations That Should Trigger Iron Studies
Classic Symptom Complex 1:
- Fatigue and weakness
- Right-upper-quadrant discomfort
- Metacarpophalangeal joint arthralgia (highly characteristic)
- Sexual dysfunction/hypogonadism
- Heart failure symptoms
- Diabetes mellitus
Physical Findings 1:
- Hepatomegaly (especially with cirrhosis)
- Skin hyperpigmentation ("bronze diabetes")
- Testicular atrophy
- Congestive heart failure
- Arthritis with chondrocalcinosis
Laboratory Clues 1:
- Unexplained elevated liver enzymes
- Incidental finding of elevated ferritin on routine screening
Most contemporary diagnoses are made incidentally through routine laboratory screening rather than overt end-organ disease. 1
Population Screening Recommendations
Routine population-wide screening is NOT recommended due to low penetrance and uncertain benefit in asymptomatic genotype-positive individuals. 1, 2
Targeted Screening IS Appropriate For 1, 2:
- First-degree relatives of confirmed cases
- Individuals with suggestive symptoms or physical findings
- Unexplained liver enzyme abnormalities
- One-time screening of asymptomatic non-Hispanic white men (highest yield)
Key Prognostic Indicators
- Serum ferritin is the most useful prognostic indicator of disease severity 4
- Only 10–50% of C282Y homozygotes develop end-organ damage, with higher penetrance in males and with increasing age 1, 2
- Women are diagnosed later than men due to menstrual blood loss 5
- Patients with cirrhosis require hepatocellular carcinoma surveillance 4, 5
Critical Diagnostic Pitfalls to Avoid
- Never screen with ferritin alone—TS is the most sensitive early marker and must be measured concurrently 1
- Normal ferritin does NOT exclude hemochromatosis in younger individuals—only 70% of C282Y homozygotes have elevated ferritin 1
- Elevated ferritin with normal TS suggests non-HFE causes of iron overload or secondary hyperferritinemia 1, 6
- Genotype alone is insufficient—biochemical iron overload must be documented 2
- Compound heterozygotes (C282Y/H63D) rarely develop significant iron overload from genetics alone—investigate other contributing factors 1