What is the management plan for a middle-aged patient of Northern European descent with a family history of hemochromatosis and suspected iron overload?

Management of Suspected Iron Overload in a Middle-Aged Northern European Patient with Family History of Hemochromatosis

This patient requires immediate HFE genetic testing and measurement of fasting transferrin saturation and serum ferritin, followed by therapeutic phlebotomy if iron overload is confirmed, with a target ferritin of 50-100 μg/L. 1

Initial Diagnostic Workup

Serum Iron Studies

• Measure fasting transferrin saturation (TS) and serum ferritin as the primary screening tests 1, 2
• TS ≥45% combined with elevated ferritin strongly suggests hemochromatosis and warrants genetic testing 2
• For men, TS >60% has 92% sensitivity and 93% specificity for hemochromatosis diagnosis; for women, the threshold is >50% 1
• Overnight fasting is essential to avoid circadian or postprandial variations that cause 80% of false-positive results 1

Genetic Testing Strategy

• HFE genetic testing is indicated when both TS ≥45% and ferritin are elevated 2
• Given Northern European descent, this patient has approximately 6.2% allelic frequency for C282Y mutation, with 0.44-0.5% risk of C282Y homozygosity 3
• More than 90% of hereditary hemochromatosis cases are C282Y homozygotes 3
• C282Y/H63D compound heterozygotes account for only 3-5% of cases and rarely develop significant iron overload 3

Risk Stratification Based on Genotype and Phenotype

If C282Y Homozygous (C282Y/C282Y)

• Proceed directly to therapeutic phlebotomy if ferritin is elevated, even without liver biopsy when ferritin <1000 μg/L and liver enzymes (ALT, AST) are normal 1
• If ferritin ≥1000 μg/L or elevated liver enzymes are present, liver biopsy should be considered to assess for cirrhosis 1
• This genotype carries 10- to 119-fold increased risk of decompensated cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy compared to age-matched controls 1, 4

If C282Y/H63D Compound Heterozygous

• Management must be guided by phenotypic presentation and presence of additional risk factors, not genotype alone 1
• Investigate for other causes of iron overload including chronic liver disease (alcoholic liver disease, NAFLD, viral hepatitis), iron-loading anemias, or transfusional iron overload 1, 2
• Phlebotomy may be considered if confirmed iron overload is documented by MRI or liver biopsy, but requires individualized clinical assessment 1
• The risk of developing significant iron overload is low in compound heterozygotes without additional environmental factors 1

If Heterozygous Carrier (C282Y/wild type or H63D/wild type)

• Carriers do not develop hereditary hemochromatosis and do not require phlebotomy 3, 2
• If iron studies are elevated in a carrier, investigate alternative causes of secondary iron overload 3, 2
• Routine screening or monitoring of asymptomatic heterozygous carriers is not recommended 3

Therapeutic Phlebotomy Protocol

Induction Phase

• Remove 1 unit (450-500 mL) of blood weekly as tolerated 1, 5
• Continue until serum ferritin reaches 50-100 μg/L (some sources suggest 10-20 μg/L for initial depletion) 1, 5
• Men should initiate phlebotomy when ferritin ≥300 μg/L; women when ferritin ≥200 μg/L 5

Maintenance Phase

• Maintain ferritin at 50-100 μg/L through periodic phlebotomy 1
• Monitor for iron reaccumulation with regular ferritin measurements 1
• Frequency of maintenance phlebotomy varies by individual iron reaccumulation rate 1

Expected Outcomes

• Survival is normal when treatment is initiated before development of cirrhosis or diabetes 1, 4
• Therapeutic phlebotomy substantially alleviates weakness, fatigue, elevated hepatic enzymes, right upper quadrant pain, and hyperpigmentation 5
• Treatment prevents progression to severe complications including cirrhosis, hepatocellular carcinoma, diabetes, hypogonadism, arthropathy, and cardiomyopathy 5, 6

Dietary Modifications

Essential Restrictions

• Avoid medicinal iron supplements and iron-fortified foods 1, 5
• Avoid vitamin C supplements as they enhance iron absorption 1, 5
• Avoid uncooked seafood to reduce risk of Vibrio infection in patients with liver disease 5
• Abstain from alcohol, which accelerates iron accumulation and liver damage 5

Recommended Dietary Pattern

• Consider a vegetarian, semi-vegetarian, or flexitarian diet to reduce heme iron intake 7
• Consume at least 600 g of vegetables and fruits daily 7
• Choose protein from legumes, fish (350-500 g/week), and lean poultry (≤200 g/week) rather than red meat from mammals 7
• Drink green or black tea, coffee, or low-fat milk with meals to inhibit iron absorption 7

Monitoring for Complications

Hepatic Assessment

• Patients with cirrhosis at diagnosis have increased risk of hepatocellular carcinoma even after iron depletion 1
• Consider liver biopsy if ferritin ≥1000 μg/L or elevated transaminases to assess for advanced fibrosis or cirrhosis 1

Endocrine and Cardiac Evaluation

• Screen for diabetes mellitus, which is both a complication and critical prognostic factor 4
• Assess for cardiomyopathy, a major cause of death in untreated hemochromatosis 4
• Evaluate for hypogonadotropic hypogonadism in symptomatic patients 5

Family Screening

First-Degree Relatives

• All first-degree relatives of confirmed hemochromatosis cases should undergo screening with transferrin saturation, ferritin, and HFE genetic testing 1
• Family-based testing is a priority prevention strategy to identify asymptomatic relatives with iron overload 8
• Genetic counseling should explain the autosomal recessive inheritance pattern and reproductive risks 3

Common Pitfalls to Avoid

• Do not assume all C282Y homozygotes will develop clinical disease - penetrance is incomplete, with only 58-70% developing progressive tissue iron overload 3, 2
• Do not overlook secondary causes of iron overload in patients who are not C282Y homozygotes 1, 2
• Do not delay treatment - the disease progresses from clinically insignificant iron accumulation (ages 0-20) to iron overload without disease (ages 20-40) to organ damage (beyond age 40) if untreated 1, 4
• Do not confuse genetic susceptibility with clinical disease - fewer than 10% of C282Y homozygotes develop end-organ manifestations 2
• Do not screen asymptomatic general populations - population screening is not recommended due to low positive predictive value and incomplete penetrance 2, 8