What is the most likely diagnosis and recommended work‑up and treatment for a patient with a normal total iron‑binding capacity, elevated serum iron, high transferrin saturation, and an increased erythrocyte sedimentation rate?

Diagnosis: Hereditary Hemochromatosis

The combination of normal TIBC, elevated serum iron, elevated transferrin saturation, and elevated ESR most strongly suggests hereditary hemochromatosis with concurrent inflammation. The normal TIBC with elevated iron and saturation is the pathognomonic biochemical signature of HFE-related hemochromatosis, while the elevated ESR indicates coexisting inflammatory disease 1, 2.

Immediate Diagnostic Work-Up

Confirm Iron Overload Pattern

Order fasting transferrin saturation and serum ferritin immediately to establish the baseline iron burden 1, 2. The transferrin saturation threshold requiring genetic testing is ≥45% in women or ≥50% in men 2, 3. Ferritin >200 µg/L (women) or >300 µg/L (men) confirms increased total body iron stores 1, 3.

Genetic Testing

Proceed directly to HFE genotyping for C282Y and H63D mutations when transferrin saturation meets the above thresholds 1, 2, 3. C282Y homozygosity accounts for 80–90% of clinically manifest hemochromatosis and confirms the diagnosis 3. C282Y/H63D compound heterozygosity produces milder overload but still requires treatment 3.

Exclude Inflammatory Causes of Elevated ESR

• Measure CRP alongside ESR to quantify the inflammatory burden 2. The combination of elevated CRP and ferritin strongly suggests secondary hyperferritinemia from inflammation 2.
• Screen for adult-onset Still's disease if ferritin rises above 4,000–5,000 ng/mL with persistent fever; measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 2.
• Evaluate for chronic inflammatory conditions including rheumatoid arthritis, inflammatory bowel disease, chronic infections, and malignancy 2.
• Check liver enzymes (AST, ALT) to assess hepatocellular injury 1, 2, 3.

Assess for End-Organ Damage

Obtain the following studies to stratify risk:

• Complete blood count to evaluate for anemia or polycythemia 2, 3
• Comprehensive metabolic panel including glucose and HbA1c to screen for diabetes 3
• Liver MRI with T2 or R2** to quantify hepatic iron concentration non-invasively 1, 3
• Electrocardiogram and echocardiography when ferritin >1,000 µg/L or cardiac symptoms are present 1, 3
• Non-invasive fibrosis scores (FIB-4 or APRI) to assess for advanced liver fibrosis 1, 2

When to Perform Liver Biopsy

Consider liver biopsy if ferritin >1,000 µg/L with elevated liver enzymes, platelet count <200,000/µL, age >40 years, or hepatomegaly 1, 2, 3. The combination of ferritin >1,000 µg/L, elevated aminotransferases, and thrombocytopenia predicts cirrhosis in ~80% of C282Y homozygotes 2, 3. A hepatic iron index >1.9 (hepatic iron concentration ÷ age) strongly suggests genetic hemochromatosis 3.

Treatment Algorithm

Therapeutic Phlebotomy (First-Line)

Initiate weekly phlebotomy of 500 mL when ferritin >300 µg/L (men) or >200 µg/L (women) with transferrin saturation >45% 3. Each session removes 200–250 mg of iron 3.

Induction phase:

• Remove 500 mL weekly until ferritin reaches 50–100 µg/L 3
• Monitor ferritin every 10–12 phlebotomies 3

Maintenance phase:

• Perform phlebotomy every 2–4 months to maintain ferritin 50–100 µg/L and transferrin saturation <50% 3
• Check ferritin every 6–12 months once stable 3

Iron Chelation (Second-Line)

Reserve deferasirox for patients who cannot tolerate phlebotomy due to severe anemia, cardiac disease, or poor venous access 3. Monitor liver and renal function regularly during chelation 3.

Lifestyle Modifications

• Avoid or strictly limit alcohol to reduce hepatotoxicity 3
• Avoid raw or undercooked shellfish because iron-overloaded patients have >50% mortality from Vibrio vulnificus septicemia 3
• Do not use iron supplements or high-dose vitamin C (>500 mg/day), which increase iron absorption 3

Family Screening

Test all first-degree relatives of C282Y homozygotes with HFE genotyping 3. C282Y homozygous relatives should have ferritin and transferrin saturation measured annually starting at age 18 3.

Critical Pitfalls to Avoid

Do not attribute hyperferritinemia solely to inflammation without evaluating transferrin saturation 2, 3. Hemochromatosis can coexist with inflammatory states, and the elevated ESR in this case may reflect concurrent inflammatory disease rather than excluding iron overload 2.

Do not delay phlebotomy awaiting liver biopsy when ferritin <1,000 µg/L and liver enzymes are normal 2, 3. Biopsy is unnecessary for initiating treatment in this scenario 3.

Do not assume H63D homozygosity or C282Y/H63D compound heterozygosity alone explains significant overload 3. Investigate additional contributors such as alcohol use, NAFLD, or other genetic mutations 3.

Elevated transferrin saturation may precede ferritin rise by years 3, 4. Do not dismiss early saturation abnormalities even when ferritin appears normal 3.

Special Consideration: Autoimmune Hepatitis

Markedly elevated transferrin saturation can simulate iron overload syndrome in autoimmune hepatitis 5. If HFE testing is negative but the phenotype suggests genetic iron overload, order a gene panel including HJV, HAMP, TFR2, SLC40A1, and CP 1, 3. Liver biopsy can guide the diagnosis when autoimmune hepatitis is suspected 5.