What are the causes and management of a high transferrin saturation ratio?

Causes of High Transferrin Saturation Ratio

Primary Iron Overload Disorders

High transferrin saturation (≥45%) most commonly indicates hereditary hemochromatosis or other primary iron overload disorders, and requires HFE genetic testing for C282Y and H63D mutations. 1

Hereditary Hemochromatosis

• HFE-related hemochromatosis is the most common cause, present in >80% of patients with clinically overt hemochromatosis, with C282Y homozygosity being the predominant genotype in individuals of European origin 1
• Compound heterozygosity (C282Y/H63D) can cause elevated transferrin saturation, though it rarely causes significant iron overload without additional acquired risk factors 2, 3

Non-HFE Hemochromatosis

• Mutations in TFR2, SLC40A1, HAMP, or HJV genes cause non-HFE hemochromatosis and should be considered when hepatic iron overload is confirmed but HFE testing is negative 2, 3
• Juvenile hemochromatosis (HJV and HAMP mutations) presents with severe, early-onset disease 2

Secondary Causes of Elevated Transferrin Saturation

Liver Disease

• Alcohol-related liver disease and cirrhosis cause decreased serum transferrin concentration, which mathematically elevates the transferrin saturation ratio 1
• Acute liver injury and acute liver failure can increase transferrin saturation and may be confused with hemochromatosis 1
• Chronic liver disease from any cause can elevate transferrin saturation due to reduced transferrin synthesis 1

Hematological Disorders

• Dyserythropoiesis (myelodysplastic syndrome, sideroblastic anemias) increases transferrin saturation due to ineffective erythropoiesis 1, 4
• Chronic hemolysis (sickle cell disease, pyruvate kinase deficiency) releases iron from lysed red blood cells 1, 4
• Transfusion-dependent anemias (thalassemia major, myelofibrosis) cause iatrogenic iron loading 4

Other Conditions

• Chronic alcohol excess increases iron absorption and can elevate both transferrin saturation and ferritin through multiple mechanisms 1
• Advanced cirrhosis reduces transferrin production, artificially elevating the saturation percentage 1

Diagnostic Approach Algorithm

Step 1: Confirm Persistent Elevation

• Repeat fasting transferrin saturation in the morning (fasting does not improve diagnostic utility, but morning samples are preferred) to confirm persistent elevation 1
• Thresholds for concern: >45% in females, >50% in males 1

Step 2: Measure Serum Ferritin

• If transferrin saturation >45% AND ferritin elevated (>200 μg/L in females, >300 μg/L in males), proceed to genetic testing 1
• If transferrin saturation >55% with normal or low ferritin, consider secondary causes first 1

Step 3: Exclude Secondary Causes

• Assess for chronic alcohol consumption through detailed history, as this is a common confounding factor 1, 3
• Check liver enzymes (ALT, AST) to evaluate for underlying liver disease 2, 3
• Measure inflammatory markers (CRP, ESR) to detect occult inflammation 2
• Screen for viral hepatitis (hepatitis B surface antigen, hepatitis C antibody) 2
• Evaluate for metabolic syndrome (BMI, waist circumference, glucose, lipids) as fatty liver disease commonly elevates ferritin 1, 2

Step 4: Genetic Testing

• Order HFE genotyping for C282Y and H63D in individuals of European origin with biochemical evidence of iron overload after informed consent 1
• If HFE testing is negative but iron overload confirmed, pursue genetic testing for non-HFE genes (TFR2, SLC40A1, HAMP, HJV) 2

Step 5: Quantify Iron Overload

• MRI with T2/T2 relaxometry* is the preferred non-invasive method to quantify hepatic iron concentration (correlation coefficient 0.74-0.98 with biochemical measurement) 5
• Liver biopsy should be considered if ferritin >1000 μg/L with elevated liver enzymes or platelet count <200,000/μL to assess for cirrhosis 2, 5

Critical Pitfalls to Avoid

• Never rely on transferrin saturation alone without ferritin, as the combination provides much greater diagnostic accuracy 2, 3
• Do not assume iron overload when transferrin saturation is elevated but <45%, as this threshold has limited specificity 1
• Recognize that transferrin saturation shows significant variability, limiting its usefulness as a single measurement 1
• Do not overlook decreased transferrin concentration (from liver disease or malnutrition) as a cause of mathematically elevated saturation 1
• Negative HFE testing does not exclude hereditary hemochromatosis, as non-HFE mutations account for significant cases 2
• Screen first-degree relatives if hereditary hemochromatosis is confirmed, as the risk of a sibling being affected is 25% 1

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 1, 6