Diagnosis: Hereditary Hemochromatosis (HFE-Related)
This elderly male with ferritin 1368 µg/L, serum iron 43.2 µmol/L, and transferrin saturation 85% has hereditary hemochromatosis until proven otherwise, and requires immediate HFE genetic testing for C282Y and H63D mutations. 1
Diagnostic Rationale
The transferrin saturation of 85% is the critical diagnostic finding here—this dramatically elevated value (normal <45% in males) indicates true iron overload rather than secondary hyperferritinemia. 1, 2
Why This is Hemochromatosis
Transferrin saturation ≥45% is the hallmark of hereditary hemochromatosis, distinguishing it from the >90% of hyperferritinemia cases caused by inflammation, liver disease, alcohol, or metabolic syndrome. 1, 2
The combination of high transferrin saturation (85%) with elevated ferritin (1368 µg/L) creates a diagnostic pattern pathognomonic for primary iron overload disorders, not secondary causes. 1, 2
In secondary hyperferritinemia (inflammation, NAFLD, alcohol), transferrin saturation is typically normal or low (<45%), not markedly elevated. 2, 3
Immediate Next Steps
Confirm the Diagnosis
Order HFE genetic testing for C282Y and H63D mutations immediately—C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE hemochromatosis. 1, 2
If HFE testing is negative, proceed to hepatic MRI with iron quantification to confirm hepatic iron overload, then consider non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV). 1, 4
Assess for Complications
Check liver enzymes (ALT, AST), platelet count, and consider liver elastography or biopsy because ferritin >1000 µg/L significantly increases cirrhosis risk. 1, 2
The combination of ferritin >1000 µg/L with elevated aminotransferases and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes. 2
Screen for diabetes (fasting glucose, HbA1c), assess for arthropathy, evaluate cardiac function (ECG, echocardiogram if indicated), and check thyroid and gonadal function. 1
Rule Out Secondary Contributors
Obtain detailed alcohol history (chronic alcohol can elevate both ferritin and transferrin saturation, though rarely to 85%). 2, 5
Check inflammatory markers (CRP, ESR) to exclude occult inflammation, though these would typically lower transferrin saturation, not raise it. 2, 4
Assess for metabolic syndrome (BMI, waist circumference, lipids, glucose) and viral hepatitis (HBsAg, anti-HCV), though these rarely cause transferrin saturation >45%. 2, 4
Treatment Initiation
If C282Y homozygote is confirmed, begin therapeutic phlebotomy immediately without waiting for liver biopsy, as the diagnosis is established and treatment prevents progression to cirrhosis, diabetes, and other complications. 1, 2
Target ferritin <50 µg/L during induction phase (weekly phlebotomy of 500 mL until target reached). 1
Maintenance phase targets ferritin <100 µg/L with phlebotomy every 2-4 months as needed. 1
Screen all first-degree relatives with transferrin saturation and ferritin, followed by HFE genetic testing if abnormal. 1, 2
Critical Pitfalls to Avoid
Never attribute this degree of transferrin saturation elevation (85%) to secondary causes alone—this level of saturation indicates primary iron overload requiring genetic evaluation. 1, 2
Do not delay genetic testing while pursuing extensive workup for secondary causes when transferrin saturation is this elevated. 2, 4
Do not overlook liver assessment when ferritin >1000 µg/L, as this threshold carries significant cirrhosis risk requiring surveillance for hepatocellular carcinoma if advanced fibrosis is present. 1, 2
Ferroportin disease (SLC40A1 mutation) typically presents with hyperferritinemia but relatively low or normal transferrin saturation (not 85%), making it less likely here. 6