What is the best course of treatment for a patient with hyperferritinemia (elevated iron), high iron saturation, and low ferritin levels, potentially indicating hemochromatosis or iron overload?

Evaluation and Management of High Iron Saturation with Low Ferritin

Immediate Diagnostic Priority

This presentation of high iron saturation with low ferritin is paradoxical and does NOT represent typical hemochromatosis—you must first exclude common causes of hyperferritinemia before pursuing genetic testing. 1

The combination you describe is unusual because:

• Classic hemochromatosis presents with BOTH elevated transferrin saturation AND elevated ferritin 1
• Low ferritin with high iron saturation suggests either laboratory error, recent blood loss, or a mixed picture requiring careful evaluation 2

Step 1: Verify Laboratory Values and Exclude Confounders

Before proceeding with any treatment decisions, you must:

• Repeat fasting transferrin saturation and ferritin to confirm the paradoxical pattern, as significant fluctuations are not typical of hemochromatosis 1
• Check for inflammation markers (CRP, ESR) since ferritin is an acute phase reactant that can be elevated by inflammation independent of iron stores 1
• Obtain liver enzymes (AST, ALT) and assess for chronic liver disease, as conditions like NAFLD, chronic hepatitis C, and alcohol-related liver disease can cause secondary iron abnormalities 1, 2
• Screen for metabolic syndrome components (BMI, blood pressure, glucose, lipids) since insulin resistance is strongly associated with hyperferritinemia even without true iron overload 3
• Assess for recent blood loss or iron supplementation history which could explain discordant values 4

Step 2: Determine If True Iron Overload Exists

Serum iron parameters alone are insufficient to diagnose iron overload—tissue iron quantification is required when the clinical picture is unclear. 1

When to Order MRI for Hepatic Iron Quantification:

• Obtain liver MRI with R2 quantification* if you have confirmed elevated transferrin saturation with unclear ferritin levels, as this non-invasively quantifies actual tissue iron stores 1
• MRI is particularly indicated when the patient lacks C282Y homozygosity or has additional risk factors like metabolic syndrome or alcohol use 1
• MRI can differentiate true hemochromatosis (predominant liver iron, minimal spleen iron) from other conditions like ferroportin disease or transfusional overload (increased spleen iron) 1

When to Consider Liver Biopsy:

• Reserve liver biopsy for assessing fibrosis if ferritin is >1,000 mcg/L or liver enzymes are elevated, NOT for diagnosing iron overload itself 1
• Biopsy is no longer necessary for diagnosis in C282Y homozygotes with straightforward presentations 1

Step 3: Genetic Testing Strategy

Only pursue HFE genetic testing if transferrin saturation is >45% (females) or >50% (males) with confirmed elevated or unclear ferritin. 1, 2

• Test for C282Y and H63D mutations if transferrin saturation meets these thresholds 1, 5
• Do NOT base diagnosis on C282Y homozygosity alone—you must have evidence of increased iron stores 1
• If genetic testing is negative for C282Y homozygosity or C282Y/H63D compound heterozygosity, investigate secondary causes of iron overload 5

Secondary Causes to Exclude:

• Hematologic disorders: thalassemia, myelodysplastic syndrome, sideroblastic anemia, sickle cell disease 5
• Chronic liver diseases: NAFLD, chronic hepatitis C, alcohol-related liver disease 1, 2, 5
• Iatrogenic: multiple transfusions, excessive iron supplementation 5

Step 4: Treatment Decision Algorithm

If True Iron Overload is Confirmed (by MRI or biopsy):

Initiate therapeutic phlebotomy with the following protocol: 1

Induction Phase:

• Remove 400-500 mL blood weekly or every 2 weeks depending on body weight and tolerance 1
• Check hemoglobin before EVERY phlebotomy session 1
• Reduce frequency if hemoglobin falls below 12 g/dL; discontinue if <11 g/dL 1
• Monitor ferritin monthly or after every 4th phlebotomy 1
• When ferritin drops below 200 mcg/L, check every 1-2 sessions 1
• Target ferritin: 50 mcg/L (most recent EASL 2022 guidelines) 1

Maintenance Phase:

• Continue phlebotomy every 1-4 months to maintain ferritin 50-100 mcg/L 1
• More relaxed targets (<200 mcg/L women, <300 mcg/L men) may be tolerated in elderly patients, though this is expert opinion only 1
• Monitor ferritin every 6 months 1
• Target transferrin saturation <60% 1

If No True Iron Overload (Normal MRI):

Do NOT initiate phlebotomy. Instead:

• Address underlying metabolic syndrome components through weight loss, dietary modification, and increased physical activity 1
• Restrict alcohol intake, especially if liver abnormalities are present 1
• Monitor iron parameters annually if C282Y/H63D compound heterozygote or H63D homozygote without overload 1

Critical Dietary and Lifestyle Modifications

Dietary changes do NOT substitute for phlebotomy but are important adjuncts: 1

• Absolutely avoid iron supplements and iron-fortified foods 1
• Avoid supplemental vitamin C, especially before iron depletion, as it accelerates iron mobilization and can increase oxidative stress 1
• Limit red meat consumption 1
• Restrict alcohol during iron depletion; abstain completely if cirrhosis is present 1
• Avoid raw or undercooked shellfish due to risk of Vibrio vulnificus infection in iron-overloaded patients 1
• Consume citrus fruits in moderation and not with meals 1

Common Pitfalls to Avoid

• Never diagnose hemochromatosis based on elevated ferritin alone—over 90% of hyperferritinemia cases are due to alcohol, inflammation, cell necrosis, tumors, or metabolic syndrome 1
• Do not over-treat with phlebotomy—ferritin <20 mcg/L significantly increases iron absorption and can cause symptomatic iron deficiency even in hemochromatosis patients 1
• Interrupt phlebotomy immediately if ferritin falls below 50 mcg/L to prevent iatrogenic iron deficiency 6
• Do not assume C282Y/H63D compound heterozygotes or H63D homozygotes need treatment—investigate for additional environmental or genetic factors if iron overload is present 1
• Transferrin saturation may remain elevated even when ferritin normalizes in hemochromatosis—this does not necessarily require more aggressive phlebotomy 1

Monitoring During Treatment

• Check folate and cobalamin periodically in patients requiring numerous phlebotomies; supplement if deficient 1
• Investigate unexpected changes in ferritin or transferrin saturation, as significant fluctuations are not characteristic of hemochromatosis 1
• Hemoglobin should not fall more than 20% from baseline during treatment 1