What is the management plan for a patient with hyperferritinemia (elevated iron levels) and increased iron saturation?

Management of Elevated Iron and Iron Saturation

The management approach depends critically on whether transferrin saturation is elevated alongside ferritin: if both are elevated, genetic testing for hemochromatosis is mandatory, followed by phlebotomy therapy if confirmed; if only ferritin is elevated with normal transferrin saturation, investigate secondary causes and avoid iron removal therapy. 1

Initial Diagnostic Evaluation

Confirm Iron Overload Pattern

• Measure both transferrin saturation (TSAT) and serum ferritin to distinguish true iron overload from hyperferritinemia without iron loading 1
• Elevated TSAT (>45% in females, >50% in males) with elevated ferritin indicates probable hemochromatosis and requires genetic testing 1, 2
• Normal or low TSAT with elevated ferritin suggests secondary causes of hyperferritinemia rather than true iron overload 2, 3

Obtain HFE Genetic Testing

• Test for C282Y and H63D mutations when TSAT is elevated (>45% in females, >50% in males) with ferritin >200 µg/L in females or >300 µg/L in males 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity with elevated TSAT and ferritin is sufficient to diagnose hemochromatosis without requiring liver biopsy 1
• Patients with elevated TSAT and ferritin but negative or heterozygous HFE testing require hepatic iron quantification by MRI to confirm iron overload 1

Assess for Secondary Causes

• Check C-reactive protein to exclude inflammatory conditions that elevate ferritin as an acute phase reactant 4, 3
• Evaluate for chronic liver disease (viral hepatitis, NAFLD, alcohol use), hematologic disorders (thalassemia, myelodysplastic syndrome), malignancy, kidney failure, and rheumatologic conditions 3, 5
• Screen for metabolic syndrome components (obesity, diabetes, hypertension, dyslipidemia), as dysmetabolic iron overload syndrome (DIOS) is the most common iron overload condition 5

Quantify Tissue Iron Burden

MRI R2* Quantification

• Perform hepatic MRI R2 to quantify liver iron concentration in patients without C282Y homozygosity or when additional risk factors are present* (metabolic syndrome, alcohol use, chronic liver disease) 1
• MRI can assess iron distribution in liver, spleen, pancreas, heart, and brain to distinguish hemochromatosis (predominantly hepatic, minimal splenic) from other causes 1
• Hepatic iron concentration on MRI predicts total body iron stores and the number of phlebotomies required for treatment 1

Consider Liver Biopsy Selectively

• Liver biopsy is indicated when serum ferritin >1,000 µg/L or liver enzymes are elevated to assess for cirrhosis, not for diagnosing iron overload itself 1
• Biopsy is not recommended if cirrhosis is already clinically evident 1

Treatment Based on Etiology

Confirmed Hemochromatosis (C282Y Homozygous or Compound Heterozygous)

• Initiate phlebotomy therapy with target ferritin <50 µg/L during induction phase and <100 µg/L during maintenance phase 1
• Perform phlebotomy weekly (typically 500 mL) during induction until target ferritin achieved 1
• Transition to maintenance phlebotomy (every 2-4 months) to maintain ferritin <100 µg/L 1
• Screen for hepatocellular carcinoma in patients with advanced fibrosis or cirrhosis, as this risk persists even after iron depletion 1

Non-HFE Iron Overload with Confirmed Hepatic Iron Loading

• Consider phlebotomy if hepatic iron concentration is significantly elevated (>3 times upper limit of normal) and patient can tolerate blood removal 1, 6
• Chelation therapy with deferasirox is reserved for patients who cannot undergo phlebotomy (anemia, severe cardiac disease) 7
• Deferasirox dosing: start 14 mg/kg/day orally once daily for patients with eGFR >60 mL/min/1.73 m² and evidence of chronic transfusional iron overload (ferritin consistently >1,000 µg/L) 7

Dysmetabolic Hyperferritinemia/DIOS

• Address underlying metabolic syndrome through weight loss, dietary modification, and increased physical activity rather than iron removal 1, 5
• Evidence for phlebotomy benefit in metabolic syndrome-associated iron overload is lacking 1
• Monitor ferritin and liver enzymes; consider phlebotomy trial only if hepatic iron concentration is markedly elevated on MRI 1, 5

Hyperferritinemia Without True Iron Overload

• Do not perform phlebotomy or iron chelation when TSAT is normal and secondary causes explain elevated ferritin 2, 3
• Treat underlying condition (inflammation, liver disease, malignancy) 3
• Serial monitoring of ferritin and TSAT every 3-6 months to ensure stability 3

Monitoring During Treatment

Phlebotomy Monitoring

• Measure serum ferritin monthly during induction phlebotomy 1
• Monitor hemoglobin before each phlebotomy session; hold if hemoglobin <11 g/dL 1
• Assess liver function tests and renal function every 3 months 1

Chelation Monitoring (if used)

• Monitor serum creatinine in duplicate, calculate eGFR, and obtain urinalysis monthly to detect renal toxicity 7
• Check serum transaminases and bilirubin monthly 7
• Perform auditory and ophthalmic examinations every 12 months 7
• Interrupt deferasirox if ferritin falls below 500 µg/L to avoid overchelation and associated toxicity 7

Critical Pitfalls to Avoid

• Never initiate iron removal therapy based on elevated ferritin alone without confirming elevated TSAT and true tissue iron overload 2, 3
• Do not assume H63D homozygosity causes clinically significant iron overload; these patients rarely develop hepatic iron loading 1
• Avoid phlebotomy in patients with anemia or functional iron deficiency (low TSAT despite elevated ferritin from inflammation) 1, 8
• Do not continue aggressive iron removal when ferritin approaches normal range, as overchelation causes serious toxicity including renal failure, especially in elderly and pediatric patients 9, 7
• Recognize that ferritin >1,000 µg/L with normal TSAT almost never represents hemochromatosis and requires investigation for secondary causes 2, 6