What is the appropriate management for a 40-year-old female patient with hyperferritinemia, high transferrin saturation, and other abnormal iron studies?

Hereditary Hemochromatosis: Immediate Therapeutic Phlebotomy Required

This 40-year-old woman has laboratory findings diagnostic of hereditary hemochromatosis (transferrin saturation 84%, serum iron 206 mg/dL) and requires immediate initiation of weekly therapeutic phlebotomy to prevent irreversible organ damage including cirrhosis, diabetes, cardiomyopathy, and arthropathy. 1, 2

Diagnostic Confirmation

Your patient's iron panel is pathognomonic for primary iron overload:

• Transferrin saturation of 84% (normal <45%) is the hallmark distinguishing hereditary hemochromatosis from secondary causes of hyperferritinemia 1, 3
• The combination of markedly elevated transferrin saturation with high serum iron creates a diagnostic pattern specific for primary iron overload disorders, not inflammatory or secondary causes 3

Immediate Next Steps

Order HFE genetic testing immediately for C282Y and H63D mutations to confirm HFE hemochromatosis, which accounts for >95% of cases 3, 4. For patients of Northern European descent, HFE testing has the highest pre-test probability and should be performed first 3.

Obtain complete iron panel including serum ferritin if not already done, as this is essential for risk stratification 1, 3. The ferritin level will determine whether liver biopsy is needed before starting phlebotomy.

Risk Stratification Based on Ferritin Level

If Ferritin <1000 μg/L:

• Begin therapeutic phlebotomy immediately without liver biopsy if liver enzymes are normal, no hepatomegaly, and age <40 years 1, 2
• Risk of advanced liver fibrosis is very low (negative predictive value 94%) with ferritin <1000 μg/L and normal transaminases 5, 1

If Ferritin >1000 μg/L:

• Check liver enzymes (ALT, AST) and platelet count urgently 1, 3
• If ferritin >1000 μg/L with elevated transaminases and platelets <200,000/μL, cirrhosis risk approaches 80% and liver biopsy is strongly recommended before starting phlebotomy 1, 3
• Consider liver elastography or MRI with iron quantification as non-invasive alternatives 5, 3

Assessment for Organ Damage

Cardiac evaluation is critical with severe iron overload:

• Obtain ECG and echocardiography to screen for arrhythmias and cardiac dysfunction 5, 3
• If any signs or symptoms of heart disease (conduction abnormalities, contractile dysfunction), proceed immediately to cardiac MRI for myocardial iron quantification without delaying phlebotomy treatment 5, 3

Screen for diabetes mellitus as iron overload causes pancreatic beta-cell damage 2

Evaluate for arthropathy, particularly affecting the 2nd and 3rd metacarpophalangeal joints, ankles, hips, and wrists, as 86.5% of hemochromatosis patients report joint pain 5, 3

Therapeutic Phlebotomy Protocol

Induction Phase:

• Remove 500 mL blood weekly until target ferritin is achieved 1, 2
• Check hemoglobin/hematocrit before each session 1, 2
• Decrease frequency if hemoglobin drops to <12 g/dL; temporarily discontinue if <11 g/dL 2
• Allow hemoglobin to fall no more than 20% from baseline 1
• Check ferritin every 10-12 phlebotomies 1
• Target ferritin: 50 ng/mL (some guidelines accept 50-100 ng/mL range) 1, 2

Maintenance Phase:

• Once target ferritin achieved, continue maintenance phlebotomy every 1-4 months as needed 1, 2
• Maintain ferritin in 50-100 ng/mL range 1, 2
• Monitor ferritin every 6 months during maintenance 2

Critical Lifestyle Modifications

Avoid all vitamin C supplements as they accelerate iron mobilization, increase oxidative stress, and can precipitate cardiac dysrhythmias during phlebotomy 1, 2

Avoid iron supplements entirely 1, 2

Avoid raw shellfish due to risk of Vibrio vulnificus infection in iron-overloaded patients 1

Limit red meat consumption, restrict alcohol intake, and avoid iron-fortified foods to prevent accelerated organ damage 2

Family Screening

Screen all first-degree relatives with transferrin saturation, ferritin, and HFE genetic testing 1, 3, 2. Penetrance is higher in family members than the general population, making screening particularly important 1.

Expected Outcomes

Therapeutic phlebotomy initiated before development of cirrhosis and diabetes significantly reduces morbidity and mortality 1. Treatment prevents progression to cirrhosis, hepatocellular carcinoma, diabetes, hypogonadism, and cardiomyopathy when started early 1, 2. However, established cirrhosis will not reverse, though progression can be halted 1. Arthropathy and hypogonadism typically do not respond to phlebotomy 2.

Common Pitfall to Avoid

Do not delay treatment while awaiting genetic testing results if clinical presentation is classic for hemochromatosis with transferrin saturation >45% and elevated ferritin 1, 3. While alcoholic hepatitis can occasionally mimic iron overload with elevated transferrin saturation 6, a transferrin saturation of 84% is highly specific for primary iron overload and warrants immediate action.