What is the most likely diagnosis and appropriate workup and management for a patient with low unsaturated iron‑binding capacity (95 µg/dL), high serum iron (202 µg/dL), high transferrin saturation (68 %), and markedly elevated ferritin (1390 ng/mL)?

Hereditary Hemochromatosis with Markedly Elevated Iron Stores

This patient has hereditary hemochromatosis (HFE-related) requiring immediate HFE genetic testing and therapeutic phlebotomy. The combination of transferrin saturation 68% (well above the 45% threshold), serum iron 202 µg/dL, low UIBC 95 µg/dL, and markedly elevated ferritin 1390 ng/mL creates a diagnostic pattern that is pathognomonic for primary iron overload, not secondary hyperferritinemia 1, 2.

Why This Is Iron Overload, Not Inflammation

The transferrin saturation of 68% is the single most critical discriminator here. When TS ≥45%, you must suspect primary iron overload and proceed immediately to genetic testing—over 90% of elevated ferritin cases with TS <45% are due to inflammation, liver disease, or metabolic syndrome, but this patient's TS is far above that threshold 1, 2. The low UIBC (95 µg/dL, well below the normal range of ~250-400 µg/dL) confirms that iron-binding capacity is saturated, which does not occur in inflammatory states where ferritin rises but TS typically drops 3, 4.

In inflammatory conditions, ferritin rises as an acute-phase reactant while hepcidin blocks iron release from storage sites, creating elevated ferritin with low TS (<20%), the exact opposite of this patient's pattern 1, 4. This patient's pattern—high iron, high TS, low UIBC, high ferritin—indicates the iron regulatory system has failed to prevent iron accumulation, which is the hallmark of hereditary hemochromatosis 1, 2.

Immediate Diagnostic Workup

Order HFE genetic testing for C282Y and H63D mutations immediately 1, 2. C282Y homozygosity or C282Y/H63D compound heterozygosity will confirm HFE-related hereditary hemochromatosis 5, 1. This is not optional—the American Association for the Study of Liver Diseases explicitly recommends HFE genotyping when TS ≥45% 1, 2.

Simultaneously obtain:

• Complete metabolic panel including ALT, AST, alkaline phosphatase, bilirubin, and albumin to assess for hepatocellular injury and synthetic function 1, 2
• Complete blood count with platelets—platelet count <200,000/µL predicts cirrhosis in 80% of C282Y homozygotes when combined with ferritin >1000 µg/L and elevated transaminases 1, 2
• Fasting glucose and lipid panel to assess for diabetes and metabolic complications 2
• Prothrombin time/INR to evaluate synthetic liver function 2

Risk Stratification by Ferritin Level

This patient's ferritin of 1390 ng/mL crosses the critical 1000 µg/L threshold that changes management. Ferritin >1000 µg/L is associated with 20-45% prevalence of cirrhosis in C282Y homozygotes 1, 2. Below 1000 µg/L with normal liver enzymes, the negative predictive value for advanced fibrosis is 94%, but this patient is above that threshold 1, 2.

**If liver enzymes are elevated OR platelet count is <200,000/µL, strongly consider liver biopsy or non-invasive fibrosis assessment (liver elastography or MRI with iron quantification) to stage liver disease** 1, 2. The combination of ferritin >1000 µg/L, elevated aminotransferases, and platelets <200,000/µL predicts cirrhosis in 80% of C282Y homozygotes 1, 2.

If the patient is <40 years old with normal liver enzymes, no hepatomegaly, and no other concerning features, you can proceed directly to therapeutic phlebotomy without liver biopsy 2.

Therapeutic Phlebotomy Protocol

Once C282Y homozygosity is confirmed, initiate therapeutic phlebotomy immediately with a target ferritin of 50-100 µg/L 2. Do not wait for liver biopsy results if the patient meets criteria for immediate treatment 2.

Induction Phase:

• Remove 500 mL of blood weekly or biweekly as tolerated 2
• Check hemoglobin/hematocrit before each phlebotomy—do not allow hemoglobin to fall more than 20% from baseline 2
• Check ferritin every 10-12 phlebotomies to monitor progress toward the 50-100 µg/L target 2
• Continue until ferritin reaches 50-100 µg/L 2

Maintenance Phase:

• Once target ferritin is achieved, continue maintenance phlebotomy every 2-4 months to keep ferritin in the 50-100 µg/L range 2
• Monitor ferritin monthly initially, then every 3 months once stable 2

Critical Dietary Restrictions:

• Avoid all iron supplements entirely 2
• Avoid vitamin C supplementation during phlebotomy therapy—it accelerates iron mobilization and increases oxidative stress 2
• Avoid raw shellfish—iron-overloaded patients have increased risk of Vibrio vulnificus infection 2

Assessment for Organ Damage

Given the ferritin level of 1390 ng/mL, assess for end-organ complications:

• Cardiac evaluation with ECG and echocardiography to screen for arrhythmias and cardiac dysfunction—iron deposition in myocardium causes restrictive cardiomyopathy, conduction abnormalities, and arrhythmias 5, 2
• Joint examination, particularly 2nd and 3rd metacarpophalangeal joints, ankles, hips, and wrists—86.5% of hemochromatosis patients report joint pain 2
• Screen for diabetes—fasting glucose and HbA1c 2
• Assess for hypogonadism if clinically indicated 5

If there are signs or symptoms of heart disease, do not delay phlebotomy while awaiting cardiac MRI—begin treatment immediately 2.

Family Screening

Screen all first-degree relatives with both HFE genotype testing and phenotype (ferritin and transferrin saturation) 2. Penetrance is higher in family members than in the general population, making cascade screening highly effective 1.

Expected Outcomes

Therapeutic phlebotomy prevents hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadism, arthropathy, and cardiomyopathy when initiated before severe iron overload develops 2. However, it does not reverse established cirrhosis, only prevents progression 2. This is why early diagnosis and treatment are critical.

Common Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload—ferritin is an acute-phase reactant elevated in inflammation, liver disease, and malignancy independent of iron stores 1, 2
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 1
• Do not overlook liver biopsy in patients with ferritin >1000 µg/L and abnormal liver tests—this combination warrants histologic assessment for cirrhosis 1, 2
• Do not delay treatment while awaiting cardiac MRI in patients with signs of heart disease 2