What are the causes of elevated iron studies (elevated serum iron, transferrin saturation, ferritin, or decreased total iron‑binding capacity)?

Causes of Elevated Iron Studies

Elevated iron studies result from either primary iron overload disorders (most commonly hereditary hemochromatosis), secondary iron overload from hematologic or liver diseases, or hyperferritinemia without true iron overload due to inflammation, malignancy, or metabolic conditions. 1

Primary Iron Overload: Hereditary Hemochromatosis

Hereditary hemochromatosis is the most common genetic cause of elevated transferrin saturation (>45% in women, >50% in men) and elevated ferritin (>200 μg/L in women, >300 μg/L in men). 1

• The condition is inherited in an autosomal recessive pattern, most commonly due to HFE gene mutations (p.C282Y homozygosity or p.C282Y/p.H63D compound heterozygosity). 1
• Biochemical findings include elevated transferrin saturation as the earliest abnormality, followed by rising ferritin and potentially elevated liver transaminases. 1
• Clinical manifestations in advanced cases include liver disease (cirrhosis, hepatocellular carcinoma), diabetes mellitus, arthropathy (particularly affecting the second and third metacarpophalangeal joints), cardiac arrhythmias, hypogonadism, and bronze skin pigmentation. 1
• Genotyping for p.C282Y should be performed in individuals of European origin with biochemical evidence of iron overload (females with transferrin saturation >45% and ferritin >200 μg/L; males with transferrin saturation >50% and ferritin >300 μg/L). 1

Secondary Iron Overload

When HFE genetic testing is negative for C282Y homozygous or C282Y/H63D compound heterozygous mutations, secondary causes of iron overload must be considered. 2

Hematologic Disorders

• Thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, and pyruvate kinase deficiency all cause iron overload through dyserythropoiesis, chronic hemolysis, or transfusion requirements. 1, 2
• These conditions are characterized by decreased serum transferrin concentration, leading to elevated transferrin saturation despite the underlying pathology. 1

Iatrogenic Causes

• Chronic transfusion therapy leads to transfusion-dependent secondary iron overload. 2
• Excessive iron supplementation, particularly intravenous iron administration, can cause iatrogenic iron overload. 2

Chronic Liver Disease

• Alcohol-related liver disease and cirrhosis cause elevated transferrin saturation through decreased serum transferrin concentration. 1
• Chronic alcohol excess increases serum ferritin by enhancing iron absorption and causing liver injury. 1
• Fatty liver disease (metabolic dysfunction-associated steatotic liver disease) commonly presents with elevated ferritin without true iron overload. 1, 3

Hyperferritinemia Without True Iron Overload

Serum ferritin is not only a marker of iron stores but also an acute-phase reactant, tumor marker, and indicator of cellular necrosis—making it frequently elevated in conditions without actual iron overload. 1, 4, 5

Inflammatory and Infectious Conditions

• Acute and chronic inflammation elevate ferritin as an acute-phase reactant while simultaneously decreasing transferrin (and thus TIBC), resulting in low or normal transferrin saturation despite high ferritin. 1, 4, 5
• Rheumatic conditions such as adult-onset Still's disease and hemophagocytic lymphohistiocytosis cause marked hyperferritinemia. 2
• Infections trigger ferritin release from macrophages, making it a marker of clinical severity rather than iron stores in critically ill patients. 5

Malignancy

• Various cancers cause elevated ferritin as a tumor marker or through cellular necrosis. 2
• Interestingly, prostate cancer is associated with lower ferritin and transferrin saturation compared to healthy controls, contrasting with other malignancies. 6

Metabolic Syndrome and Fatty Liver

• Metabolic syndrome components (obesity, insulin resistance, dyslipidemia) commonly cause dysmetabolic hyperferritinemia with normal or only mildly elevated transferrin saturation. 1, 3
• This pattern (high ferritin with transferrin saturation <45%) should prompt evaluation for metabolic liver disease rather than hemochromatosis. 3

Kidney Disease

• Chronic kidney disease causes hyperferritinemia through multiple mechanisms including inflammation and impaired iron utilization. 2, 4
• In CKD patients, ferritin >800 ng/mL with transferrin saturation <20% represents functional iron deficiency with an inflammatory iron block rather than true overload. 4

Diagnostic Algorithm

The first step in evaluating elevated iron studies is measuring transferrin saturation and serum ferritin simultaneously. 1

1. If transferrin saturation >45% (women) or >50% (men) with elevated ferritin: Proceed with HFE genotyping for p.C282Y and p.H63D mutations. 1

2. If HFE testing is negative: Evaluate for secondary iron overload by assessing for hematologic disorders (complete blood count, peripheral smear, hemolysis markers), transfusion history, and chronic liver disease. 2

3. If ferritin is elevated but transferrin saturation is normal or low (<45%): This pattern indicates hyperferritinemia without true iron overload—evaluate for inflammation (C-reactive protein), malignancy, metabolic syndrome, chronic liver disease, or kidney disease. 1, 3, 4

4. Measure serum iron and TIBC for additional differential diagnosis information, recognizing these have significant day-to-day variability and are influenced by diurnal variation, recent meals, and inflammation. 1

Critical Pitfalls to Avoid

• Do not diagnose hemochromatosis based on elevated ferritin alone—transferrin saturation must also be elevated, and genetic testing is required for confirmation. 1, 3
• Do not overlook secondary causes when genetic testing is negative—hematologic disorders and chronic liver disease are common culprits. 2
• Recognize that ferritin elevation in the setting of inflammation, infection, or critical illness does not reflect iron stores and should not trigger iron depletion therapy. 4, 5
• Fatty liver disease and metabolic syndrome are extremely common causes of mild ferritin elevation (typically 200-1000 μg/L) with normal transferrin saturation and must be distinguished from true iron overload. 1, 3
• Serum iron and TIBC have poor diagnostic accuracy due to high variability—do not rely on these values alone for diagnosis. 1