What are the therapeutic phlebotomy parameters (blood volume per draw, frequency, target serum ferritin, target transferrin saturation, hemoglobin thresholds, and maintenance schedule) for hereditary hemochromatosis?

Therapeutic Phlebotomy Parameters for Hereditary Hemochromatosis

Remove 500 mL of whole blood weekly or biweekly until serum ferritin reaches 50–100 μg/L, then continue maintenance phlebotomy every 1–4 months to keep ferritin in that same range. 1, 2

Initial Iron Depletion Phase

Volume and Frequency

• Remove 500 mL (one unit) of whole blood per session, which contains approximately 200–250 mg of iron 1, 2
• Perform phlebotomy weekly or biweekly as tolerated during the depletion phase 1, 2
• The depletion phase typically requires 2–3 years for patients with significant iron overload (>30 g total body iron) 2

Hemoglobin Monitoring Before Each Session

• Check hemoglobin or hematocrit before every phlebotomy to prevent excessive anemia 1, 2
• Stop phlebotomy if hemoglobin falls below 11 g/dL and reassess the patient's clinical status 2
• Reduce phlebotomy frequency or volume if hemoglobin falls below 12 g/dL 2, 3
• Do not allow hemoglobin/hematocrit to decline by more than 20% of baseline 1, 2

Ferritin Monitoring During Depletion

• Check serum ferritin every 10–12 phlebotomies (approximately every 3 months or monthly) during initial depletion 1, 2
• When ferritin drops below 200 μg/L, increase monitoring to every 1–2 phlebotomy sessions to avoid overshooting into iron deficiency 2, 3
• Stop frequent phlebotomy when serum ferritin reaches 50–100 μg/L 1, 2

Target Ferritin at End of Depletion

• The American Association for the Study of Liver Diseases recommends 50–100 μg/L as the target range 1, 2, 3
• The European Association for the Study of the Liver recommends approximately 50 μg/L during induction 3
• Do not reduce ferritin below 50 μg/L, as this represents the physiologic lower limit for adequate iron stores and will paradoxically increase dietary iron absorption even in hemochromatosis patients 3

Maintenance Phase

Frequency and Monitoring

• Continue phlebotomy every 1–4 months to maintain ferritin between 50–100 μg/L 1, 2
• The frequency must be individualized based on each patient's iron reaccumulation rate, which varies significantly among individuals 2
• Untreated patients typically accumulate approximately 100 μg/L of ferritin per year, which guides the maintenance interval 2, 3
• Check serum ferritin every 6 months during maintenance to adjust the phlebotomy schedule 2, 3
• Continue checking hemoglobin/hematocrit before each maintenance phlebotomy 2

Transferrin Saturation Considerations

• Transferrin saturation may remain elevated (>50%) despite achieving target ferritin levels 3
• While specific target levels for transferrin saturation lack evidence-based support, observational data suggest that general and joint symptoms may persist with long-term transferrin saturation >50% even when ferritin is controlled 3
• Periodic transferrin saturation monitoring is advised, though it should not drive treatment decisions as aggressively as ferritin 3

Special Populations and Safety Considerations

Patients with Cardiac Disease

• Patients with cardiomyopathy or cardiac arrhythmias require slower phlebotomy schedules because rapid iron mobilization increases the risk of sudden cardiac death 1, 2
• Rapid mobilization creates a toxic low-molecular-weight chelate pool of iron that can precipitate fatal arrhythmias 1, 2

Elderly Patients

• More relaxed maintenance targets (ferritin <200 μg/L for women, <300 μg/L for men) may be better tolerated in elderly patients, though this is based on expert opinion rather than clinical trials 3, 4

Patients with Mild Elevation

• For C282Y homozygotes with ferritin <1000 μg/L and normal liver enzymes, prophylactic phlebotomy is still favored because treatment is safe, inexpensive, and no reliable indicators exist to predict who will develop complications 1

Dietary and Supplement Recommendations

Critical Restrictions

• Avoid vitamin C supplements entirely during phlebotomy treatment, particularly in iron-loaded patients, as vitamin C accelerates iron mobilization to potentially dangerous levels that can saturate transferrin and increase pro-oxidant activity 1, 2
• Do not use iron supplements or consume iron-fortified foods while undergoing phlebotomy 2

Optional Dietary Modifications

• Dietary adjustments are generally unnecessary because the amount of iron absorption affected by a low-iron diet (2–4 mg/day) is negligible compared to the 200–250 mg removed per phlebotomy session 1, 2
• Limit red meat intake and restrict alcohol consumption during the depletion phase, especially in patients with cirrhosis who should abstain completely 3
• Avoid raw shellfish due to reports of Vibrio vulnificus infections in hemochromatosis patients 1

Nutrient Monitoring

• Periodically assess plasma folate and cobalamin, especially in patients undergoing numerous phlebotomies, and initiate supplementation when deficiencies are identified 3

Common Pitfalls and How to Avoid Them

Overshooting into Iron Deficiency

• The most critical error is continuing phlebotomy when ferritin falls below 50 μg/L, which triggers increased dietary iron absorption and can cause symptomatic iron deficiency 3
• When ferritin drops below 200 μg/L, intensify monitoring to every 1–2 sessions to catch the target range before overshooting 2, 3
• If ferritin falls below 500 μg/L during maintenance, interrupt therapy immediately and do not resume until ferritin rises above the target range 4

Inadequate Hemoglobin Monitoring

• Failure to check hemoglobin before each session can lead to severe anemia 1, 2
• The 11 g/dL and 12 g/dL hemoglobin cutoffs provide clear decision points that minimize both overtreatment and undertreatment 2

Unexplained Ferritin Fluctuations

• Any unexpected changes in serum ferritin or transferrin saturation should be investigated, as significant fluctuations are atypical for hereditary hemochromatosis and may indicate concurrent inflammation, infection, or other pathology 3