What labs and investigations should be ordered next for an adult male with an isolated elevated ferritin level?

Elevated Ferritin in an Adult Male: Next Steps

Order a fasting transferrin saturation (TS) immediately—this single test determines whether you are dealing with true iron overload (TS ≥45%) requiring genetic testing, or secondary hyperferritinemia (TS <45%) from inflammation, liver disease, or metabolic causes. 1, 2

Initial Laboratory Panel

Obtain these tests simultaneously with transferrin saturation:

• Fasting transferrin saturation (morning sample preferred) 3, 1
• Complete metabolic panel including AST, ALT, bilirubin, albumin to assess hepatocellular injury 1
• Complete blood count with differential to evaluate for anemia, polycythemia, or hematologic malignancy 1, 4
• Inflammatory markers: CRP and ESR to detect occult inflammation 1
• Creatine kinase to evaluate for muscle necrosis 1
• Fasting glucose and lipid panel to assess for metabolic syndrome 1

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

This pattern indicates possible hereditary hemochromatosis or other primary iron overload disorders. 3, 1, 2

• Order HFE genetic testing for C282Y and H63D mutations immediately 3, 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE hemochromatosis 3, 1
• Consider liver MRI to quantify hepatic iron concentration if genetic testing is positive 1
• Liver biopsy should be considered if ferritin >1000 μg/L with elevated liver enzymes, hepatomegaly, age >40 years, or platelet count <200,000/μL 3, 1

The combination of ferritin >1000 μg/L, elevated aminotransferases, and platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes. 3, 1

If TS <45%: Evaluate Secondary Causes

Iron overload is excluded with >90% certainty when TS <45%—do NOT order HFE genetic testing. 1, 2 Over 90% of elevated ferritin cases are caused by non-iron-overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD. 1, 2

Evaluate these common secondary causes systematically:

1. Liver Disease (Most Common)

• Obtain detailed alcohol history using validated tools (AUDIT-C) 1
• Order abdominal ultrasound to evaluate for fatty liver, chronic liver disease, and 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
• Use FIB-4 or NAFLD Fibrosis Score to stratify fibrosis risk non-invasively 1

2. Inflammatory Conditions

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant 1
• If ferritin >4,000-5,000 ng/mL with persistent fever, measure glycosylated ferritin fraction (<20% is 93% specific for adult-onset Still's disease) 1
• If ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction, consider hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1

3. Malignancy

• Solid tumors and lymphomas are common causes of extreme hyperferritinemia 5, 6
• Assess for B symptoms (fever, night sweats, weight loss), lymphadenopathy, and consider CT imaging if suspected 1

4. Cell Necrosis

• Elevated CK indicates muscle injury releasing ferritin from lysed cells 1
• Acute hepatitis causes hepatocellular necrosis with ferritin release 1

Risk Stratification by Ferritin Level

Ferritin Level	Clinical Significance	Action Required
<1,000 μg/L	Low risk of organ damage; 94% negative predictive value for advanced fibrosis [3,1,2]	No liver biopsy needed if TS <45% and liver enzymes normal [1]
1,000-10,000 μg/L	Higher risk of advanced fibrosis/cirrhosis if iron overload present [1]	Consider liver biopsy if TS ≥45% with elevated liver enzymes or thrombocytopenia [3,1]
>10,000 μg/L	Rarely represents simple iron overload; urgent specialist referral required [1,6]	Evaluate for life-threatening conditions (malignancy, severe inflammatory syndromes, hemophagocytic lymphohistiocytosis) [1,5,6]

Critical Pitfalls to Avoid

Never use ferritin alone without transferrin saturation to diagnose iron overload—ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 3, 1, 2

Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin. 1, 2

Do not order HFE genetic testing when TS <45%—this leads to misdiagnosis and inappropriate phlebotomy. 1, 2

Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests—this combination warrants histologic assessment for cirrhosis. 3, 1

Recognize that alcoholic hepatitis can mimic iron overload with severely elevated ferritin and TS >45% due to disrupted iron metabolism, not true iron overload. 7

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, 6
• Confirmed TS ≥45% on repeat testing 1
• Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly) 1
• C282Y homozygosity confirmed requiring therapeutic phlebotomy 3, 1