What are the potential causes of elevated iron studies, such as increased serum iron, transferrin saturation, and ferritin?

Causes of Elevated Iron Studies

Elevated iron studies—including increased serum iron, transferrin saturation, and ferritin—are most commonly caused by inflammation, chronic liver disease (especially alcohol-related and non-alcoholic fatty liver disease), metabolic syndrome, malignancy, and tissue necrosis, accounting for over 90% of cases in outpatients, rather than hereditary hemochromatosis. 1

Primary Iron Overload Disorders

Hereditary hemochromatosis is the most important genetic cause to identify, though it represents a minority of elevated iron studies:

• HFE-related hemochromatosis occurs in approximately 3–5 per 1,000 individuals, with C282Y homozygosity being most common among non-Hispanic white persons (prevalence 0.44%) 1
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hereditary hemochromatosis 2, 1
• Non-HFE hemochromatosis involves mutations in TFR2, SLC40A1, HAMP, or HJV genes 1
• Ferroportin disease is an autosomal dominant condition characterized by iron overload with elevated serum ferritin 3

Secondary Causes of Elevated Iron Studies

Liver Disease

The most common hepatic causes include:

• Chronic alcohol consumption increases intestinal iron absorption and causes hepatocellular injury, leading to elevated ferritin and transferrin saturation 1
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload 3, 1
• Viral hepatitis (hepatitis B and C) 1
• Acute hepatitis with hepatocellular necrosis 1
• Cirrhosis from any cause 1

Inflammatory and Rheumatologic Conditions

Ferritin rises as an acute-phase reactant in:

• Chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease 1
• Adult-onset Still's disease (AOSD) with extreme hyperferritinemia (4,000–30,000 ng/mL) and glycosylated ferritin fraction <20% 3, 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3
• Systemic inflammatory response syndrome 1
• Active infections cause ferritin to rise acutely as part of the inflammatory response 3, 1

Hematologic Disorders

Secondary iron overload from:

• Thalassemia syndromes requiring chronic transfusions 4
• Myelodysplastic syndrome 4
• Myelofibrosis 4
• Sickle cell disease (especially with transfusion therapy) 4, 5
• Sideroblastic anemias 4
• Pyruvate kinase deficiency 4

Malignancy

• Solid tumors 1
• Lymphomas 1
• Hepatocellular carcinoma 1

Other Causes

• Metabolic syndrome independent of NAFLD 3, 1
• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells 1
• Chronic kidney disease 3
• Diabetes mellitus 1

Critical Diagnostic Algorithm

The single most important test is transferrin saturation (TS), which must be measured simultaneously with ferritin to differentiate true iron overload from secondary causes. 1

When TS ≥45%:

• Suspect primary iron overload and proceed immediately with HFE genetic testing for C282Y and H63D mutations 2, 1
• Consider liver MRI to quantify hepatic iron concentration 1
• If ferritin >1,000 μg/L with elevated liver enzymes or platelet count <200,000/μL, consider liver biopsy 1

When TS <45%:

• Iron overload is unlikely—over 90% of cases are due to secondary causes 1
• Evaluate for chronic alcohol consumption, inflammatory conditions, liver disease, metabolic syndrome, and malignancy 1
• Do NOT proceed with genetic testing for hemochromatosis 1

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L has a 94% negative predictive value for advanced liver fibrosis and indicates low risk of organ damage 3, 1

Ferritin 1,000–10,000 μg/L in the setting of confirmed iron overload (TS ≥45%) indicates higher risk of advanced fibrosis/cirrhosis; the combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200,000/μL predicts cirrhosis in ~80% of C282Y homozygotes 3, 1

Ferritin >10,000 μg/L rarely represents simple iron overload and mandates urgent specialist referral to evaluate for life-threatening conditions such as hemophagocytic lymphohistiocytosis or severe inflammatory syndromes 3, 1

Common Pitfalls to Avoid

Never interpret ferritin alone without transferrin saturation—ferritin is an acute-phase reactant that rises with inflammation, infection, liver disease, malignancy, and tissue necrosis independent of actual iron stores 3, 1

Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin under these circumstances 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 extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload and requires urgent evaluation for alternative diagnoses 3