Hemochromatosis (Hereditary Hemochromatosis)
Diagnostic Workup
Begin with serum transferrin saturation (TSAT) and serum ferritin as your initial screening tests 1. These iron parameters form the cornerstone of diagnosis and guide all subsequent management decisions.
Initial Laboratory Assessment
For patients with suspected hemochromatosis:
Measure TSAT and ferritin first
- TSAT >45% in females or >50% in males/postmenopausal women warrants further investigation
- Ferritin >200 μg/L in females or >300 μg/L in males/postmenopausal women suggests iron overload 2
Proceed to HFE genetic testing when iron parameters are elevated
Critical Pitfall to Avoid
Elevated ferritin occurs in many conditions beyond hemochromatosis—including acute/chronic liver disease, inflammatory states, and other iron overload syndromes 3. Do not assume hemochromatosis based on ferritin alone. The combination of elevated TSAT with elevated ferritin in the appropriate genetic context confirms the diagnosis.
Assessment of End-Organ Damage
All patients require non-invasive liver fibrosis assessment at diagnosis 1:
- Transient elastography can rule out advanced fibrosis if liver stiffness <6.4 kPa 1
- FIB-4 score is the best-validated serum marker for fibrosis staging, though evidence in hemochromatosis specifically is limited 1
- Patients with ferritin <1,000 μg/L, normal transaminases, and no hepatomegaly have very low risk of advanced fibrosis 1
Evaluate for extrahepatic manifestations 1:
- Joint pain, arthritis, osteoporosis, fractures
- Diabetes and other endocrine dysfunction
- Reproductive/sexual dysfunction (erectile dysfunction, loss of libido, amenorrhea)
- In severe iron overload: ECG and echocardiography for arrhythmia and cardiac dysfunction 1
- In juvenile hemochromatosis: cardiac MRI for myocardial iron quantification 1
Treatment
Therapeutic phlebotomy is the first-line treatment for all patients with hemochromatosis and evidence of iron overload 1. This simple intervention prevents or reverses organ damage when initiated early 4, 3.
Phlebotomy Protocol
Induction Phase
Target: Serum ferritin of 50 μg/L (but not lower to avoid iron deficiency) 1. This is a strong recommendation based on the 2022 EASL guidelines.
- Volume and frequency: 400-500 mL weekly or every 2 weeks, depending on body weight and tolerance 1
- Monitor hemoglobin before each session:
- Monitor ferritin monthly (or after every 4th phlebotomy) 1
- When ferritin drops below 200 μg/L, check every 1-2 sessions until target reached 1
Maintenance Phase
Target: Serum ferritin 50-100 μg/L with some flexibility 1. In elderly patients or those who tolerate lower targets poorly, more relaxed targets (<200 μg/L for women, <300 μg/L for men) may be acceptable, though this is based on expert opinion rather than clinical studies 1.
- Frequency: Every 1-4 months (typically 2-6 phlebotomies per year), depending on individual iron accumulation rate 1
- Monitor ferritin every 6 months to maintain target range 1
- Continue hemoglobin monitoring before each session 1
- Lifelong treatment required 1
Important Monitoring Considerations
Transferrin saturation monitoring remains controversial 1. TSAT often remains elevated (>50%) even when ferritin is at target. Recent evidence suggests that persistently elevated TSAT may correlate with symptoms like fatigue and joint pain, and consideration should be given to including TSAT as a therapeutic target 5. However, evidence-based TSAT targets are lacking in current guidelines 1.
Check plasma folate and cobalamin periodically, especially in patients requiring numerous phlebotomies; supplement if deficient 1.
Alternative Treatment Options
Erythrocytapheresis
Erythrocytapheresis is an effective alternative to phlebotomy, particularly in the induction phase where it requires fewer procedures and is cost-effective 1. It causes fewer hemodynamic changes and is the preferred option in selected cases 1.
Iron Chelation Therapy
Use only when phlebotomy is not feasible (inaccessible veins, needle phobia, concomitant anemia, life-threatening cardiac iron overload) 1.
Deferasirox (DFX) has the most evidence as a second-line option 1
Deferoxamine (DFO) and deferiprone (DFP) have very limited evidence in hemochromatosis 1
- DFP carries risk of agranulocytosis and should only be prescribed by specialists 1
In juvenile hemochromatosis with life-threatening cardiac iron overload, combination chelation therapy (oral DFP + intravenous DFO) may be necessary alongside or instead of phlebotomy 1.
Dietary and Lifestyle Modifications
Dietary modifications do not substitute for iron removal therapy 1. However, specific restrictions help reduce iron accumulation:
Strong Recommendations
- Avoid iron supplementation and iron-fortified foods 1
- Avoid supplemental vitamin C, especially before iron depletion (vitamin C enhances iron absorption and may act as a pro-oxidant in iron overload) 1
- If supplementation is necessary for other reasons, limit to 500 mg daily 1
- Limit red meat consumption (heme iron is well absorbed and less regulated in hemochromatosis) 1
- Restrict alcohol intake during iron depletion phase 1
- Patients with iron overload and/or liver abnormalities should avoid or consume very little alcohol
- Patients with cirrhosis must abstain completely 1
Additional Considerations
- Consume fruit juices and citrus fruits in moderation, not with meals (vitamin C content enhances iron absorption) 1
- Avoid raw or undercooked shellfish and wound exposure to seawater (risk of Vibrio vulnificus infection, which is particularly dangerous in iron-overloaded patients) 1
Surveillance for Complications
Hepatocellular Carcinoma (HCC) Screening
All patients with cirrhosis require HCC screening every 6 months, regardless of iron depletion status 1. This is a 100% consensus recommendation.
- Screening method: Abdominal ultrasound by experienced personnel 1
Consider HCC screening every 6 months in patients with advanced fibrosis (F3/bridging fibrosis), regardless of iron depletion 1.
Even if fibrosis regresses to F2 or less after treatment, continue HCC screening (though surveillance interval may be individualized) 1.
Key Point on HCC Risk
Additional risk factors (alcohol consumption, type 2 diabetes, viral hepatitis) modify HCC risk in hemochromatosis patients with advanced fibrosis, but validated risk scores are not available 1.
Special Populations
Pregnancy
- Avoid iron deficiency in patients planning pregnancy 1
- In pregnant women with mild-to-moderate iron overload without advanced liver disease, phlebotomy can be paused during pregnancy in most patients 1
- Management depends on liver disease stage and extrahepatic manifestations 1