What is the appropriate work‑up and management for a 69‑year‑old woman with markedly elevated serum iron, low unsaturated iron‑binding capacity, low total iron‑binding capacity, high transferrin saturation, very high ferritin, and elevated vitamin B12, who is not taking any supplements?

Evaluation of Markedly Elevated Iron Indices with High Ferritin and B12

This patient has iron overload, not iron deficiency, and requires immediate evaluation for hereditary hemochromatosis and secondary causes of iron accumulation.

Understanding the Laboratory Pattern

Your patient's iron studies demonstrate a classic iron overload pattern:

• Transferrin saturation of 73% far exceeds the normal range of 20–50% and the iron overload threshold of >50%, confirming that transferrin is nearly saturated with iron 1
• Low TIBC of 234 mg/dL reflects suppressed transferrin synthesis in response to iron excess, the opposite of iron deficiency where TIBC rises 2
• Low UIBC of 63 mg/dL indicates almost no vacant iron-binding sites remain on transferrin 2
• Ferritin of 1123 ng/mL is markedly elevated and, combined with transferrin saturation >50%, strongly suggests true iron overload rather than inflammation alone 3
• Vitamin B12 of 2760 pg/mL is substantially elevated and may reflect underlying liver disease, myeloproliferative disorder, or malignancy 4

Mandatory Initial Work-Up

1. Hereditary Hemochromatosis Screening

Genetic testing for HFE mutations (C282Y and H63D) is the single most important next step because this patient's transferrin saturation >55% and ferritin >300 ng/mL meet diagnostic criteria for hemochromatosis evaluation 3.

• Order HFE gene mutation analysis looking specifically for C282Y homozygosity or C282Y/H63D compound heterozygosity 3
• A transferrin saturation of 73% has 88–91% sensitivity for detecting clinically significant HFE mutations 5, 6
• The combination of elevated ferritin and transferrin saturation in this range makes hereditary hemochromatosis the leading diagnosis until proven otherwise 3

2. Hepatic Assessment

Liver biopsy or advanced imaging is required when ferritin exceeds 1000 ng/mL in the setting of confirmed HFE mutations to assess hepatic iron concentration and exclude significant fibrosis 3.

• Obtain comprehensive metabolic panel including AST, ALT, alkaline phosphatase, bilirubin, albumin, and INR to evaluate liver synthetic function 3
• Consider abdominal MRI with T2 sequences* to quantify hepatic iron concentration non-invasively 3
• Liver biopsy with Prussian blue staining and atomic absorption spectrometry remains the gold standard when hepatic iron concentration >1701 μg/g dry weight is suspected 3

3. Cardiac Evaluation

Iron overload cardiomyopathy must be excluded given the ferritin level and potential for cardiac iron deposition 3.

• Order electrocardiogram to screen for conduction abnormalities, first-degree AV block, or arrhythmias that correlate with atrial iron deposition 3
• Obtain echocardiogram to assess for restrictive physiology, diastolic dysfunction, or dilated cardiomyopathy with systolic dysfunction 3
• Consider cardiac MRI with T2 sequences* if echocardiogram shows any abnormality, as cardiac iron deposition can be patchy and missed on biopsy 3

4. Hematologic Evaluation

Complete blood count with differential and peripheral smear are essential to evaluate for:

• Myeloproliferative disorders (which can cause both elevated ferritin and markedly elevated B12) 3, 4
• Myelodysplastic syndrome (ferritin has prognostic value in MDS) 3
• Macrocytic anemia or dysplastic features requiring bone marrow examination 3

Serum B12 of 2760 pg/mL warrants specific investigation because extreme elevations are associated with malignancy (most common), liver disease, and myeloproliferative disorders rather than supplementation 4.

5. Exclude Secondary Iron Overload

Obtain a detailed history focusing on:

• Transfusion history: Even 10 or more transfusions without chelation can cause iron overload 7
• Alcohol consumption: Chronic alcohol use increases iron absorption and can elevate ferritin 3
• Chronic liver disease: Hepatitis C, NAFLD, and cirrhosis can cause iron accumulation 3
• Inflammatory conditions: Measure C-reactive protein to determine if ferritin elevation reflects inflammation versus true iron overload 2

Diagnostic Algorithm

Step 1 – Confirm Iron Overload:

• Transferrin saturation >50% + ferritin >300 ng/mL = iron overload until proven otherwise 3

Step 2 – Genetic Testing:

• Order HFE mutation analysis (C282Y, H63D) 3

Step 3 – If C282Y Homozygote or C282Y/H63D Compound Heterozygote:

• Proceed to liver biopsy or hepatic MRI when ferritin >1000 ng/mL 3
• Assess for cirrhosis and hepatocellular carcinoma risk 3

Step 4 – If HFE Mutations Negative:

• Evaluate for secondary causes: transfusion history, chronic liver disease, myelodysplastic syndrome, thalassemia, sideroblastic anemia 3
• Consider bone marrow biopsy with iron staining if MDS suspected 3

Step 5 – Cardiac and Endocrine Screening:

• ECG and echocardiogram for all patients with ferritin >1000 ng/mL 3
• Screen for diabetes, hypogonadism, and hypothyroidism (common endocrine complications of iron overload) 3

Treatment Considerations

Therapeutic phlebotomy is first-line therapy for hereditary hemochromatosis once diagnosis is confirmed 3.

• Target ferritin <50 ng/mL and transferrin saturation <50% 3
• Initial phlebotomy schedule: 500 mL weekly until ferritin normalizes 3
• Maintenance phlebotomy every 2–4 months to maintain target ferritin 3

Iron chelation therapy is reserved for patients who cannot tolerate phlebotomy or have transfusion-dependent iron overload 7.

Critical Pitfalls to Avoid

• Do not assume elevated ferritin is solely due to inflammation when transferrin saturation is >50%; this pattern indicates true iron overload requiring genetic testing 3
• Do not delay HFE mutation testing in patients with transferrin saturation >55% and ferritin >200–300 ng/mL, as early diagnosis prevents cirrhosis and hepatocellular carcinoma 3
• Do not overlook cardiac evaluation in patients with ferritin >1000 ng/mL, as iron overload cardiomyopathy has <1 year survival with severe dysfunction 3
• Do not dismiss markedly elevated B12 (>2000 pg/mL) as benign; it frequently signals malignancy, liver disease, or myeloproliferative disorder requiring investigation 4
• Do not rely on serum iron alone for diagnosis, as it has high day-to-day variability; transferrin saturation and ferritin are far more reliable 2, 1