In an otherwise healthy adult with total iron‑binding capacity 163 µg/dL, serum iron 116 µg/dL, and ferritin 283 ng/mL, what is the most likely diagnosis and recommended evaluation?

Hemochromatosis (Iron Overload)

This patient has laboratory findings consistent with hemochromatosis or iron overload: transferrin saturation of 71% (serum iron 116 ÷ TIBC 163 × 100) and ferritin 283 ng/mL, both exceeding diagnostic thresholds for iron overload evaluation.

Diagnostic Interpretation

Transferrin Saturation Analysis

• Transferrin saturation >45% is the primary screening threshold for hemochromatosis and warrants further genetic testing. 1
• This patient's calculated TSAT of 71% far exceeds the 45% cutoff, indicating marked iron overload rather than deficiency. 1
• The extremely low TIBC of 163 µg/dL (normal range approximately 250–400 µg/dL) reflects near-complete saturation of transferrin with iron, a hallmark of iron overload states. 1

Ferritin Interpretation

• Ferritin 283 ng/mL exceeds the screening threshold of >250 µg/L in men or >200 µg/L in women used to identify C282Y homozygotes in primary care populations. 1
• In the HEIRS study, elevated ferritin (>300 µg/L in men, >200 µg/L in women) was present in 57% of female and 88% of male C282Y homozygotes. 1
• Ferritin >150 µg/L rarely occurs with absolute iron deficiency, even in the presence of inflammation, making iron overload the primary diagnostic consideration. 2

Why This Is NOT Iron Deficiency

• Iron deficiency is characterized by low serum iron, elevated TIBC (typically >400 µg/dL), low transferrin saturation (<20%), and low ferritin (<30 ng/mL). 3
• This patient demonstrates the opposite pattern: normal-to-high serum iron, markedly reduced TIBC, extremely elevated TSAT, and elevated ferritin—all consistent with iron overload. 1
• In iron overload conditions, UIBC may be decreased or near zero as transferrin becomes saturated with iron. 3

Recommended Evaluation

Immediate Genetic Testing

• All patients with transferrin saturation >45% and elevated ferritin should undergo HFE gene testing for C282Y and H63D mutations. 1
• C282Y homozygosity is the most common genetic cause of hereditary hemochromatosis in individuals of European ancestry. 1
• In patients of non-European origin with clinical suspicion and elevated TSAT/ferritin, direct sequencing of HFE and non-HFE genes (HJV, TFR2, CP, SLC40A1) may be considered. 1

Assessment of Organ Involvement

• Obtain liver function tests (AST, ALT) and consider non-invasive fibrosis assessment (FIB-4 score, APRI score) to evaluate for hepatic iron deposition and fibrosis. 1
• Patients with severe iron overload should be evaluated for arrhythmia and cardiac dysfunction with electrocardiogram and echocardiography. 1
• Screen for diabetes mellitus (fasting glucose or HbA1c), as pancreatic iron deposition can cause glucose intolerance. 1
• Assess for arthropathy, particularly involving the 2nd and 3rd metacarpophalangeal joints, which is characteristic of hemochromatosis and affects 86.5% of patients. 1

Liver Imaging and Biopsy Considerations

• Serum ferritin levels have additional value as a predictor of advanced fibrosis and cirrhosis in confirmed hemochromatosis. 1
• Liver biopsy may be indicated when ferritin is markedly elevated (>1000 µg/L) or when non-invasive markers suggest advanced fibrosis, to quantify hepatic iron concentration and assess for cirrhosis. 1

Differential Diagnosis Beyond Hereditary Hemochromatosis

Secondary Iron Overload

• Chronic liver disease (alcoholic liver disease, chronic hepatitis B/C, nonalcoholic fatty liver disease) can elevate ferritin in the absence of true iron overload. 1
• Inflammatory conditions, lymphomas, and chronic inflammatory states can raise ferritin independently of iron stores. 1
• Measure C-reactive protein to identify concurrent inflammation, because inflammation can falsely elevate ferritin. 3

Non-HFE Hemochromatosis

• Juvenile hemochromatosis (HJV, HAMP mutations) presents with severe iron overload at a younger age and requires cardiac MRI for myocardial iron quantification. 1
• Ferroportin disease (SLC40A1 mutations) and transferrin receptor 2 mutations (TFR2) are rarer causes that may present with elevated ferritin and TSAT. 1

Treatment Implications

Phlebotomy Therapy

• If genetic testing confirms hemochromatosis, therapeutic phlebotomy (removal of 500 mL blood weekly) is the first-line treatment to reduce iron stores. 1
• Target ferritin <50 µg/L during the depletion phase, then maintain ferritin 50–100 µg/L with maintenance phlebotomy. 1

Monitoring and Complications

• Joint disease and osteoporosis are common in hemochromatosis (86.5% report arthritis/joint pain) and do not respond uniformly to phlebotomy, requiring specific orthopedic management. 1
• Patients with hemochromatosis have increased risk of hip replacement (HR 2.77) and knee replacement (HR 2.14) compared to the general population. 1

Critical Pitfalls to Avoid

• Do not misinterpret low TIBC as a sign of iron deficiency; in the context of high serum iron and high ferritin, low TIBC indicates transferrin saturation and iron overload. 1, 3
• Do not delay genetic testing in patients with TSAT >45% and elevated ferritin, as early diagnosis and treatment prevent irreversible organ damage (cirrhosis, diabetes, cardiomyopathy). 1
• Do not attribute elevated ferritin solely to inflammation without calculating transferrin saturation; TSAT >45% points to true iron overload requiring hemochromatosis evaluation. 1
• Do not assume normal liver enzymes exclude significant hepatic iron deposition; non-invasive fibrosis markers and imaging are required for comprehensive assessment. 1