In a 50‑year‑old man with markedly elevated ferritin (~999 µg/L) and transferrin saturation 43 %, what is the appropriate evaluation and management for suspected iron overload?

Evaluation and Management of Elevated Ferritin with Borderline-Elevated Transferrin Saturation

Immediate Interpretation

Your patient's transferrin saturation of 43% falls just below the 45% threshold that triggers genetic testing for hereditary hemochromatosis, making primary iron overload unlikely; the ferritin elevation of 999 µg/L most probably reflects secondary causes such as metabolic syndrome, fatty liver disease, chronic alcohol use, or occult inflammation rather than true iron overload. 1, 2

Diagnostic Algorithm

Step 1: Confirm the Transferrin Saturation Result

• Repeat fasting transferrin saturation in the morning to account for day-to-day variability, which is substantial for this parameter 2
• If the repeat TSAT remains **<45%**, iron overload is excluded with >90% certainty and you should pivot to evaluating secondary causes 1, 2
• If the repeat TSAT rises to ≥45%, proceed immediately to HFE genetic testing for C282Y and H63D mutations 1, 2

Step 2: Evaluate Secondary Causes (When TSAT <45%)

The combination of ferritin 999 µg/L with TSAT 43% strongly suggests a secondary cause rather than hereditary hemochromatosis. Over 90% of elevated ferritin cases in this TSAT range are due to chronic alcohol consumption, inflammation, cell necrosis, tumors, or metabolic syndrome/NAFLD—not iron overload. 1

Essential Laboratory Panel

• Comprehensive metabolic panel including ALT, AST, bilirubin, albumin, and glucose to assess hepatocellular injury and metabolic dysfunction 1
• Inflammatory markers: CRP and ESR to detect occult inflammation 1
• Lipid panel and hemoglobin A1c to screen for metabolic syndrome 1
• Complete blood count with differential to evaluate for hematologic malignancy or polycythemia 1
• Creatine kinase if muscle injury is suspected 1

Imaging

• Abdominal ultrasound is the standard initial imaging study to evaluate for fatty liver, chronic liver disease, hepatomegaly, or other structural abnormalities 1
  • Nearly 40% of adults with abnormal liver tests have fatty liver on ultrasound 1
  • If ultrasound shows steatosis and alcohol consumption is not excessive, diagnose NAFLD 1

Detailed History

• Quantify alcohol consumption precisely; chronic alcohol increases iron absorption and causes hepatocellular injury 1
• Screen for metabolic risk factors: obesity, diabetes, hypertension, dyslipidemia 1, 3
• Review medications and supplements that may elevate ferritin 1
• Assess for symptoms of malignancy: weight loss, night sweats, lymphadenopathy 1

Step 3: Risk Stratification by Ferritin Level

Your patient's ferritin of 999 µg/L sits just below the critical 1,000 µg/L threshold that changes management. 1

• Ferritin <1,000 µg/L has a 94% negative predictive value for advanced hepatic fibrosis, meaning liver biopsy is not indicated if liver enzymes are normal and TSAT remains <45% 1, 4
• Ferritin >1,000 µg/L combined with elevated aminotransferases or platelet count <200,000/µL predicts cirrhosis in 80% of C282Y homozygotes and warrants liver biopsy 1
• Ferritin >10,000 µg/L rarely represents simple iron overload and requires urgent specialist referral for life-threatening conditions such as hemophagocytic lymphohistiocytosis or adult-onset Still's disease 1

Step 4: Specific Diagnostic Considerations

If Elevated Liver Enzymes Are Present

• The combination of ferritin 999 µg/L with elevated ALT and normal TSAT strongly suggests non-alcoholic fatty liver disease (NAFLD) or metabolic syndrome 1
• Use non-invasive fibrosis scores (FIB-4 or NAFLD Fibrosis Score) to stratify risk 1
• Do not perform phlebotomy; the treatment target is the underlying liver disease, not the ferritin itself 1

If Inflammatory Markers Are Elevated

• CRP >5 mg/L indicates active inflammation and explains ferritin elevation independent of iron stores 1
• If ferritin continues rising or exceeds 4,000–5,000 ng/mL with persistent fever, measure glycosylated ferritin fraction (<20% is 93% specific for adult-onset Still's disease) 1
• Screen for macrophage activation syndrome if clinical suspicion exists (persistent fever, splenomegaly, cytopenias, elevated triglycerides) 1

If Metabolic Syndrome Is Present

• Ferritin elevation in metabolic syndrome reflects hepatocellular injury and insulin resistance rather than true iron overload 1, 3
• Weight loss and metabolic control are the primary interventions, not iron reduction 1
• Patients with hyperferritinemia, normal TSAT, and multiple metabolic alterations (insulin resistance, dyslipidemia, hyperuricemia) are at high risk for NASH 3

Management Strategy

When TSAT Remains <45%

Do not proceed with phlebotomy or iron chelation. 1 The ferritin elevation is a marker of the underlying condition, not the therapeutic target.

• Treat the underlying disease:

  • Weight loss and lifestyle modification for NAFLD/metabolic syndrome 1
  • Alcohol cessation if chronic alcohol use is identified 1
  • Disease-specific anti-inflammatory therapy for inflammatory conditions 1
  • Oncologic treatment if malignancy is discovered 1

• Monitor ferritin trends every 3–6 months to ensure levels stabilize or decline with treatment of the underlying condition 1

When TSAT Rises to ≥45% on Repeat Testing

• Order HFE genetic testing for C282Y and H63D mutations immediately 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 1
• If genetic testing confirms hemochromatosis:
  • Initiate therapeutic phlebotomy without liver biopsy if age <40 years, normal liver enzymes, and ferritin <1,000 µg/L 1
  • Consider liver biopsy if ferritin >1,000 µg/L with elevated liver enzymes, age >40 years, hepatomegaly, or platelet count <200,000/µL 1
  • Screen first-degree relatives with TSAT and ferritin 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based solely on elevated ferritin without confirming TSAT ≥45% 1, 2
• Do not order HFE genetic testing when TSAT <45%, as this leads to misdiagnosis and unnecessary phlebotomy 1
• Do not overlook liver biopsy in patients with ferritin >1,000 µg/L and abnormal liver tests, as this combination warrants histologic assessment for cirrhosis 1
• Recognize that ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2
• Do not assume hereditary hemochromatosis when TSAT is elevated; conditions such as alcoholic hepatitis or acute liver injury can produce identical laboratory patterns 1

When to Refer to Specialist

Refer to hepatology or hematology if:

• Ferritin >1,000 µg/L with elevated bilirubin 1
• Ferritin >10,000 µg/L regardless of other findings 1
• Confirmed TSAT ≥45% on repeat testing 1
• Clinical evidence of cirrhosis (platelet count <200,000/µL, elevated bilirubin, hepatomegaly) 1
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy 1
• Cause of elevated ferritin remains unclear after initial workup 5

Bottom Line

In a 50-year-old man with ferritin 999 µg/L and TSAT 43%, the most likely diagnosis is secondary hyperferritinemia from metabolic syndrome, fatty liver disease, or chronic alcohol use rather than hereditary hemochromatosis. Repeat the fasting TSAT; if it remains <45%, focus your workup on liver imaging, metabolic screening, and inflammatory markers rather than genetic testing. Treat the underlying condition—not the ferritin number itself—and reserve phlebotomy only for confirmed iron overload with TSAT ≥45%. 1, 2, 4, 5, 3