In an adult patient not taking iron supplements, what does an isolated ferritin level of 570 ng/mL indicate and what initial work‑up and treatment steps are recommended?

Ferritin 570 ng/mL: Diagnostic Approach and Management

A ferritin of 570 ng/mL in an adult not taking iron supplements most commonly reflects secondary hyperferritinemia from inflammation, liver disease, metabolic syndrome, or chronic alcohol use—not iron overload—and requires immediate measurement of fasting transferrin saturation to differentiate true iron overload (TS ≥45%) from these far more prevalent secondary causes (TS <45%). 1

Step 1: Measure Transferrin Saturation Immediately

Order a fasting transferrin saturation (TS) test without delay. This single test determines whether you are dealing with true iron overload or secondary hyperferritinemia. 1

• If TS ≥45%: Suspect primary iron overload (hereditary hemochromatosis or other iron-loading disorders) and proceed immediately to HFE genetic testing for C282Y and H63D mutations. 2, 1
• **If TS <45%**: Iron overload is excluded with >90% certainty; the elevated ferritin is an acute-phase reactant from secondary causes. 1

Critical pitfall: Never diagnose iron overload based on ferritin alone. Ferritin rises as an acute-phase reactant in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1

Step 2: If TS <45% (Most Likely Scenario)

Over 90% of elevated ferritin cases with TS <45% are caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, or metabolic syndrome/NAFLD—not hereditary hemochromatosis. 1

Evaluate Secondary Causes:

A. Liver Disease Assessment

• Check ALT, AST, and order abdominal ultrasound to evaluate for fatty liver, chronic liver disease, or hepatomegaly. 1
• Nearly 40% of adults with abnormal liver tests have fatty liver on ultrasound. 1
• If ultrasound shows fatty liver and alcohol consumption is not excessive, diagnose NAFLD and assess for metabolic risk factors (obesity, glucose intolerance, dyslipidemia). 1

B. Alcohol History

• Obtain detailed alcohol consumption history. Chronic alcohol increases iron absorption and causes hepatocellular injury, leading to elevated ferritin. 1

C. Inflammatory Markers

• Measure CRP and ESR to detect occult inflammation from rheumatologic diseases, inflammatory bowel disease, or infections. 1

D. Malignancy Screening

• Consider age-appropriate cancer screening, particularly if ferritin continues rising or exceeds 1,000 ng/mL. 3
• Malignancy was the most frequent cause in one large series of ferritin >1,000 ng/mL. 3

Step 3: If TS ≥45% (Primary Iron Overload Pathway)

Order HFE genetic testing for C282Y and H63D mutations immediately. 2, 1

• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hereditary hemochromatosis. 2, 1
• If C282Y homozygote is confirmed: Initiate therapeutic phlebotomy and screen first-degree relatives. 2

Risk Stratification by Ferritin Level:

Ferritin <1,000 µg/L (Your patient at 570 µg/L):

• Low risk of organ damage; negative predictive value of 94% for advanced hepatic fibrosis. 2, 1
• If C282Y homozygote with age <40 years, no clinical liver disease, and normal liver enzymes: therapeutic phlebotomy can begin without liver biopsy. 2

Ferritin 1,000–10,000 µg/L:

• Higher risk of advanced fibrosis/cirrhosis if iron overload is present. 1
• The combination of ferritin >1,000 µg/L, elevated aminotransferases, and platelet count <200,000/µL predicts cirrhosis in ~80% of C282Y homozygotes. 1
• Consider liver biopsy if ferritin >1,000 µg/L with elevated liver enzymes or thrombocytopenia. 2, 1

Ferritin >10,000 µg/L:

• Rarely represents simple iron overload; mandates urgent specialist referral to evaluate for life-threatening conditions (hemophagocytic lymphohistiocytosis, severe infections, acute hepatitis). 4

Step 4: Special Clinical Contexts

If ferritin rises above 4,000–5,000 ng/mL with persistent fever:

• Consider Adult-Onset Still's Disease and measure glycosylated ferritin fraction (<20% is 93% specific for AOSD). 2, 1

If ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction:

• Consider hemophagocytic lymphohistiocytosis/macrophage activation syndrome. 2

Management Strategy

For TS <45% (secondary hyperferritinemia):

• Treat the underlying condition, not the elevated ferritin itself. 1
• For NAFLD: weight loss and metabolic syndrome management. 1
• For inflammatory conditions: disease-specific anti-inflammatory therapy. 1
• For malignancy: oncologic treatment. 1
• Do not perform phlebotomy—it is only indicated for confirmed iron overload with TS ≥45%. 1

For TS ≥45% with confirmed C282Y homozygosity:

• Initiate therapeutic phlebotomy. 2
• Screen first-degree relatives with TS and ferritin. 2

When to Refer to Hepatology/Hematology

Refer if any of the following occur:

• Ferritin >1,000 µg/L with elevated bilirubin 1
• Ferritin >10,000 µg/L regardless of other findings 1
• Confirmed TS ≥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

Bottom Line

At ferritin 570 ng/mL, your immediate action is to measure transferrin saturation. If TS <45% (>90% probability), focus on identifying and treating secondary causes—liver disease, inflammation, alcohol, or metabolic syndrome. If TS ≥45%, proceed to HFE genetic testing. Do not assume iron overload without confirming TS ≥45%, as ferritin elevation at this level is far more commonly due to secondary causes than hereditary hemochromatosis. 1