What is the most likely diagnosis for a 43-year-old woman with a family history of cardiomyopathy, elevated iron (Hyperferremia) and ferritin levels, and abnormal liver enzymes (Elevated Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)), but a normal physical exam and electrocardiogram (ECG)?

Hereditary Hemochromatosis

The most likely diagnosis is hereditary hemochromatosis (HH), given the combination of elevated transferrin saturation (72%), elevated ferritin (200 μg/L in a woman), mildly elevated liver enzymes, and a family history of cardiomyopathy at a relatively young age.

Diagnostic Reasoning

Iron Studies Confirm Iron Overload

The patient's iron studies are diagnostic for iron overload:

• Transferrin saturation = 180/250 × 100 = 72%, which exceeds the diagnostic threshold of ≥45% for hemochromatosis 1
• Ferritin of 200 μg/L meets the diagnostic threshold for women (>200 μg/L) 1
• Both parameters being elevated simultaneously strongly supports the diagnosis of hereditary hemochromatosis rather than secondary hyperferritinemia 2, 3

Family History Strongly Supports HH

The father's death from cardiomyopathy at age 58 is highly consistent with undiagnosed hereditary hemochromatosis:

• Cardiac involvement in HH typically manifests in the 40s-50s and carries a poor prognosis once heart failure develops 1, 4
• The heart is one of the organs with high transferrin receptor density that demonstrates dysfunction from iron overload 1
• Cardiomyopathy develops late in the disease process, often when treatment is no longer possible 1

Liver Involvement is Expected

The mildly elevated AST (55) and ALT (49) are consistent with early hepatic iron deposition:

• A common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation 5
• The liver is one of the primary organs affected by iron overload due to high transferrin receptor density 1

Normal ECG Does Not Exclude Early Cardiac Involvement

The normal ECG and physical exam reflect the preclinical phase of cardiac involvement:

• Cardiac involvement in HH is a slow process lasting years, with impaired diastolic function and cardiac hypertrophy appearing first, followed by dilated cardiomyopathy 4
• Early cardiac abnormalities may be overlooked when patients do not present severe symptoms 4

Immediate Next Steps

Confirm Diagnosis with HFE Genetic Testing

HFE genetic testing for C282Y and H63D mutations should be performed immediately 1, 2:

• C282Y homozygosity accounts for 85-90% of clinically affected patients of European ancestry 2, 6
• Genetic testing is indicated for clinical and biochemical signs of hemochromatosis with elevated transferrin saturation and high serum ferritin 2

Screen for Cardiac Involvement

Echocardiography should be performed to detect early cardiac dysfunction before irreversible damage occurs 4:

• Speckle tracking echocardiography can detect discrete myocardial abnormalities in the preclinical phase 4
• Cardiac MRI with T2 signal assessment can identify myocardial iron infiltration and depressed LV function 1

Initiate Phlebotomy Therapy

Therapeutic phlebotomy should be initiated promptly, as it is the mainstay of treatment and can improve heart function and reduce liver complications 1, 5:

• Treatment can prevent or reverse organ damage from iron overload when started early 7
• Target ferritin during maintenance should be 50-100 μg/L 8

Critical Family Screening

All first-degree relatives (siblings, children, mother) must undergo screening with both HFE genetic testing and simultaneous phenotypic testing (transferrin saturation and ferritin) 2:

• The yield is particularly high in siblings, with 33% showing C282Y homozygosity 2
• Early identification prevents the development of end-organ damage including fatal cardiomyopathy 1

Important Clinical Pitfalls

Do not delay treatment waiting for genetic confirmation - the combination of transferrin saturation >45% and elevated ferritin in the context of family history of early cardiomyopathy is sufficient to begin phlebotomy 1, 5.

Do not attribute the father's cardiomyopathy to other causes without investigating HH - cardiac involvement is a well-established manifestation of untreated hemochromatosis and develops in the 40s-50s 1, 4.

Monitor hemoglobin at every phlebotomy session - decrease frequency if hemoglobin <12 g/dL and discontinue if <11 g/dL 8.