What is the appropriate workup for an adult patient with normal iron and ferritin levels but elevated iron saturation (hyperironsatemia) of 58%?

Workup for Elevated Iron Saturation (58%) with Normal Iron and Ferritin

An iron saturation of 58% with normal ferritin requires genetic testing for hereditary hemochromatosis (HFE gene mutations C282Y and H63D) as the primary next step, since this pattern suggests possible early hemochromatosis or altered iron metabolism rather than iron overload. 1

Initial Diagnostic Approach

Confirm the Elevated Transferrin Saturation

• Repeat fasting transferrin saturation to confirm the elevation, as this is the screening test of choice for iron overload states 1
• A fasting transferrin saturation >45% in women or >50% in men warrants further investigation 1
• Your patient's value of 58% exceeds these thresholds and requires evaluation regardless of normal ferritin 1

Proceed to Genetic Testing

Genotyping for HFE mutations (C282Y and H63D) should be performed in individuals with transferrin saturation >45% (females) or >50% (males), even with normal ferritin levels. 1

• C282Y homozygosity is the most common genetic cause of hereditary hemochromatosis 1
• C282Y/H63D compound heterozygosity can also cause iron overload, though typically milder 1
• Normal ferritin does not exclude early hemochromatosis, as ferritin rises later in disease progression 1, 2

Differential Diagnosis to Consider

If HFE Testing is Negative

Evaluate for secondary causes of elevated transferrin saturation with normal ferritin: 3, 2

• Chronic liver disease: Check liver function tests (AST, ALT, bilirubin, albumin) as hepatic dysfunction can alter transferrin synthesis 3, 2
• Dysmetabolic iron overload syndrome: Look for metabolic syndrome features including obesity, hyperlipidemia, abnormal glucose metabolism, or hypertension 4, 5
• Hematologic disorders: Consider thalassemia syndromes, myelodysplastic syndrome, or sideroblastic anemia if there are blood count abnormalities 2
• Chronic inflammatory conditions: Assess inflammatory markers (CRP, ESR) to evaluate for anemia of chronic disease, though this typically shows low transferrin saturation 3

Key Laboratory Studies to Order

Complete the following workup: 3, 2

• Complete blood count with differential to assess for anemia and red cell morphology 3
• Comprehensive metabolic panel including liver function tests and glucose 3, 2
• Inflammatory markers (CRP, ESR) to assess for chronic disease 3
• Lipid panel and hemoglobin A1c to screen for metabolic syndrome 5
• Hepatitis panel if liver disease is suspected 2

Advanced Imaging if Indicated

When to Consider MRI

Quantitative MRI (T2 or R2 relaxometry) for hepatic iron concentration should be obtained if:* 1, 2

• Genetic testing confirms C282Y homozygosity or C282Y/H63D compound heterozygosity 1
• There is clinical suspicion of iron overload despite negative HFE testing 1, 2
• Ferritin subsequently rises above 1000 µg/L, which predicts significant hepatic fibrosis 1

MRI is superior to liver biopsy for non-invasive iron quantification and can assess distribution in liver, spleen, pancreas, heart, and brain 1

Critical Pitfalls to Avoid

Do Not Assume Iron Overload

• High transferrin saturation with normal ferritin is NOT typical of established iron overload 3, 6
• Significant hepatic iron overload (>3 times upper limit of normal) is highly unlikely without HFE-related hemochromatosis or secondary causes when ferritin is normal 6
• The pattern may represent early hemochromatosis, altered iron metabolism, or decreased transferrin production rather than excess iron 3

Do Not Initiate Phlebotomy Prematurely

• Therapeutic phlebotomy should NOT be started based solely on elevated transferrin saturation 3, 7
• Phlebotomy is indicated when ferritin is ≥300 µg/L in men or ≥200 µg/L in women with confirmed hemochromatosis 7
• Your patient's normal ferritin does not meet criteria for immediate phlebotomy 7

Do Not Overlook Non-HFE Causes

• If HFE testing is negative, pursue evaluation for dysmetabolic hyperferritinemia and metabolic syndrome, which can present with this iron study pattern 4, 5
• This syndrome is characterized by hepatic iron overload with normal transferrin saturation and is strongly associated with obesity, diabetes, and hyperlipidemia 5

Monitoring Strategy

If genetic testing is negative and no secondary cause is identified: 1, 2

• Recheck transferrin saturation and ferritin every 6-12 months 1
• Monitor for development of metabolic syndrome features 5
• Consider hepatology referral if ferritin rises or liver enzymes become elevated 2