What is the appropriate workup and management for a patient with elevated ferritin and transferrin saturation (high iron levels)?

Workup and Management of Elevated Iron Levels

When you encounter elevated ferritin and transferrin saturation, immediately measure a fasting transferrin saturation (TS) if not already done, because TS ≥45% indicates true iron overload requiring genetic testing for hereditary hemochromatosis, while TS <45% points to secondary causes like inflammation, liver disease, or metabolic syndrome that should never be treated with phlebotomy. 1

Initial Diagnostic Algorithm

Step 1: Confirm Transferrin Saturation

• Measure fasting transferrin saturation simultaneously with ferritin—this single test determines whether you are dealing with true iron overload versus secondary hyperferritinemia. 1, 2
• Never interpret ferritin alone; over 90% of elevated ferritin cases are NOT due to iron overload, as ferritin rises as an acute-phase reactant in inflammation, liver disease, malignancy, and tissue necrosis independent of actual iron stores. 1, 2

Step 2: Branch Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing for C282Y and H63D mutations immediately—this confirms or excludes hereditary hemochromatosis. 1, 2, 3
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hereditary hemochromatosis. 1, 2, 3
• Check baseline liver enzymes (ALT, AST), complete metabolic panel, and complete blood count. 1

If TS <45%: Evaluate Secondary Causes

• Iron overload is excluded with >90% certainty when TS <45%. 1, 2
• Check inflammatory markers (CRP, ESR) to detect occult inflammation. 1
• Assess liver function (ALT, AST, bilirubin, albumin) to evaluate for chronic liver disease including NAFLD, alcoholic liver disease, or viral hepatitis. 1, 2
• Consider abdominal ultrasound to detect fatty liver, hepatomegaly, or cirrhotic morphology. 2
• Evaluate for metabolic syndrome components: obesity, glucose intolerance, dyslipidemia, hypertension. 1, 2

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis. 1, 2
• In confirmed C282Y homozygotes with TS ≥45%, age <40 years, normal liver enzymes, and no hepatomegaly, initiate therapeutic phlebotomy without liver biopsy. 1

Ferritin 1000–10,000 μg/L

• Consider liver biopsy if ferritin >1000 μg/L AND elevated liver enzymes OR platelet count <200,000/μL—this combination predicts cirrhosis in 80% of C282Y homozygotes. 1, 2
• Alternative: use liver MRI with T2/T2* relaxometry to quantify hepatic iron concentration non-invasively. 1
• Assess for cardiac involvement with ECG and echocardiography if severe iron overload suspected. 1

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—urgent specialist referral required to evaluate for life-threatening conditions. 1, 2
• Consider adult-onset Still's disease (measure glycosylated ferritin fraction; <20% is 93% specific for AOSD). 1, 2
• Evaluate for hemophagocytic lymphohistiocytosis or macrophage activation syndrome (fever, splenomegaly, cytopenias, elevated triglycerides). 1

Management Based on Diagnosis

Hereditary Hemochromatosis (C282Y Homozygote with TS ≥45%)

Therapeutic Phlebotomy Protocol: 1

• Remove 500 mL blood weekly or biweekly as tolerated
• Check hemoglobin/hematocrit before each session; allow hemoglobin to fall no more than 20% from baseline
• Check ferritin every 10–12 phlebotomies
• Target ferritin 50–100 μg/L for induction phase
• Once target achieved, transition to maintenance phlebotomy every 2–4 months

Dietary Restrictions: 1

• Avoid iron supplements entirely
• Avoid vitamin C supplementation (accelerates iron mobilization and increases oxidative stress)
• Avoid raw shellfish (risk of Vibrio vulnificus infection in iron-overloaded patients)
• Limit red meat and iron-fortified cereals

Family Screening: 1

• Screen all first-degree relatives with TS, ferritin, and HFE genetic testing regardless of symptoms

Secondary Hyperferritinemia (TS <45%)

Treat the underlying condition, NOT the elevated ferritin: 1, 2

• NAFLD/Metabolic Syndrome: Weight loss, metabolic control, address insulin resistance—ferritin reflects hepatocellular injury and insulin resistance, not iron overload. 1, 2
• Chronic Alcohol Use: Abstinence—ferritin decreases rapidly during abstinence (from ~1483 to ~388 μg/L within 1.5–6 weeks). 4
• Inflammatory Conditions: Disease-specific anti-inflammatory therapy. 1
• Chronic Kidney Disease with Functional Iron Deficiency: If ferritin 500–1200 μg/L but TS <25%, IV iron may still be beneficial for anemia management despite elevated ferritin. 1, 5

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload—this is the single most common error. 1, 2
• Do not order HFE genetic testing when TS <45%—this leads to misdiagnosis and unnecessary phlebotomy. 2
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests—histology is needed to confirm cirrhosis. 1, 2
• Do not perform phlebotomy for secondary hyperferritinemia—it will not improve outcomes and may worsen anemia. 1
• Do not delay treatment while awaiting cardiac MRI in patients with severe hemochromatosis and signs of heart disease. 1

Indications for Specialist Referral

Refer to gastroenterology/hepatology or hematology when: 1, 2

• Ferritin >1000 μg/L with elevated bilirubin
• Ferritin >10,000 μg/L regardless of other findings
• Confirmed TS ≥45% on repeat testing
• Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly)
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy
• Evidence of cardiac or endocrine organ damage