What causes high transferrin saturation in patients with a history of iron metabolism disorders or multiple blood transfusions?

Causes of High Transferrin Saturation

High transferrin saturation (≥45%) is most commonly caused by hereditary hemochromatosis (HFE-related), but secondary causes including chronic liver disease, alcohol-related liver disease, and multiple blood transfusions must be systematically excluded. 1

Primary Iron Overload Disorders

HFE-related hereditary hemochromatosis is the predominant cause of elevated transferrin saturation in individuals of European descent, present in >80% of patients with clinically overt hemochromatosis. 2 The condition results from:

• C282Y homozygosity – the most common genotype causing hereditary hemochromatosis 2, 1
• C282Y/H63D compound heterozygosity – a less penetrant but clinically significant mutation pattern 2, 1

Non-HFE hereditary hemochromatosis accounts for a minority of cases and includes mutations in: 2

• Hemojuvelin (HJV) gene – causing juvenile hemochromatosis with rapid iron accumulation 2
• Transferrin receptor-2 (TfR2) gene 2
• Ferroportin (SLC40A1) gene 2
• Hepcidin (HAMP) gene 2

Secondary Causes of Elevated Transferrin Saturation

Chronic Liver Disease

Alcohol-related liver disease and cirrhosis cause decreased serum transferrin concentration, which mathematically elevates the transferrin saturation ratio even without true iron overload. 1, 3 This represents a critical diagnostic pitfall where transferrin saturation can exceed 45% despite the absence of hereditary hemochromatosis. 3

Chronic liver disease from any etiology elevates transferrin saturation due to reduced hepatic transferrin synthesis, including: 1

• Non-alcoholic fatty liver disease (NAFLD) 2, 4
• Hepatitis B 2
• Hepatitis C 2
• Cirrhosis from any cause 2

Transfusional Iron Overload

Multiple blood transfusions represent a major iatrogenic cause of iron overload in patients with: 2

• Thalassemia major and other thalassemia syndromes 2, 5
• Sickle cell disease 2, 5
• Myelodysplastic syndrome 5
• Aplastic anemia 2
• Chronic hemolytic anemias 2

Each unit of packed red blood cells contains 200-250 mg of elemental iron that accumulates progressively since the body lacks active iron excretion mechanisms. 2

Hematologic Disorders with Ineffective Erythropoiesis

Increased gastrointestinal iron absorption occurs in conditions with ineffective erythropoiesis: 2

• Sideroblastic anemia 2, 5
• Severe thalassemia (even without transfusions) 2
• Pyruvate kinase deficiency 2, 5
• Myelofibrosis 5

Hereditary Hypotransferrinemia

Genetic mutations in the transferrin (TF) gene cause paradoxically elevated transferrin saturation despite low total transferrin levels. 6 When combined with HFE or HAMP mutations, this can lead to clinically significant iron overload. 6

Diagnostic Algorithm

Step 1: Confirm persistent elevation by repeating fasting transferrin saturation in the morning, with thresholds for concern being >45% in females and >50% in males. 1

Step 2: Measure serum ferritin simultaneously. If transferrin saturation >45% AND ferritin elevated (>200 μg/L in females, >300 μg/L in males), proceed to genetic testing. 1 Never rely on transferrin saturation alone without ferritin, as the combination provides much greater diagnostic accuracy. 1

Step 3: Order HFE genetic testing for C282Y and H63D mutations if both parameters are elevated. 1, 5

Step 4: If HFE testing is negative for C282Y homozygosity or C282Y/H63D compound heterozygosity, systematically evaluate secondary causes: 5

• Obtain detailed alcohol consumption history 3, 4
• Check liver enzymes (AST, ALT) and hepatitis serologies 5
• Assess for metabolic syndrome components (glucose, lipids, BMI) 4
• Review transfusion history 2, 5
• Evaluate for hematologic disorders (CBC with differential, reticulocyte count) 5

Step 5: Consider liver MRI for hepatic iron quantification or liver biopsy if liver disease is suspected as the cause of iron overload. 5

Critical Pitfalls to Avoid

Do not assume hereditary hemochromatosis based solely on elevated transferrin saturation. Transferrin saturation >45% has high sensitivity but low specificity and positive predictive value, frequently identifying patients with alcoholic liver disease, hepatitis, or other acute causes of elevated ferritin. 3, 7

Recognize that transferrin saturation shows significant day-to-day variability, limiting its usefulness as a single measurement. 1 Morning fasting samples are preferred for accuracy. 1

In patients with low or normal transferrin saturation but elevated ferritin, consider dysmetabolic hyperferritinemia, inflammatory conditions, malignancy, or non-HFE iron overload disorders rather than classic hemochromatosis. 7

Avoid unnecessary phlebotomy in patients with alcoholic hepatitis who may present with severely elevated transferrin saturation and ferritin mimicking hereditary hemochromatosis. 3 Treat the underlying liver disease first. 3

Mortality Risk

Transferrin saturation >55% is associated with significantly increased all-cause mortality (hazard ratio 1.60,95% CI 1.17-2.21), with deaths more commonly attributed to cirrhosis and diabetes consistent with iron overload complications. 2, 1