Thoracic Pathology: A Volume in the High Yield Pathology Series 1st Edition

Cardiac Hemochromatosis


• Excessive iron in cardiomyocytes with tissue damage and impaired organ function


• Hereditary disease: most common mutation is in HFE gene close to HLA-A locus on chromosome 6

  • Other rare gene mutations: hepcidin, transferrin receptor 2 (TfR2), hemojuvelin

• Secondary disease: due to iron-loading (ineffective erythropoiesis) anemias, such as thalassemia and sideroblastic anemia, or excessive transfusion or iron therapy

Clinical features


• One of the most common autosomal recessive diseases

  • HFE mutation in northern Europeans: approximately 10% carriers; 0.5% homozygous

    – C282Y >80% of above

    – H63D homozygous → no disease

    – C282Y/H63D compound heterozygous → disease

  • About 90% of homozygous patients will have iron overloading

    – About 30% of men but only 1% of women progress to symptomatic disease

    – Women are protected by menstrual blood loss


• Rarely evident before 20 years

• By 40 to 60 years, organ damage starts manifesting in decreasing frequency as follows:

  • Liver: cirrhosis (landmark for irreversible disease)

  • Pancreas: diabetes mellitus

  • Synovial joints: arthritis

  • Heart: cardiomyopathy

  • Anterior pituitary: hypogonadotropic hypogonadism

• Cardiac complications:

  • About 15% of hemochromatosis cases have cardiomyopathy; more common in juvenile variants

  • Cardiac arrhythmias

  • Sudden onset, rapidly progressive congestive heart failure

  • Often misdiagnosed as idiopathic cardiomyopathy

• General diagnostic tests:

  • Transferrin saturation

  • HFE mutation (screen all first-degree relatives)

  • Ferritin levels and liver function panel

  • Liver biopsy: score for cirrhosis and iron level

  • Hepatic iron concentration by MRI

• Diagnostic test for cardiomyopathy:

  • Transthoracic echocardiography for diastolic dysfunction

  • Noninvasive measurement of cardiac iron content by MRI GE T2∗ technique

  • Endomyocardial biopsy (will miss diagnosis if disease is patchy or subepicardial)

Prognosis and treatment

• Treatment for hemochromatosis (also treat heart failure)

  • Therapeutic phlebotomy

  • Iron chelation (and dietary restrictions)

    – IV desferrioxamine

    – Oral deferasirox

• With iron depletion therapy, 5-year survival rate of hemochromatosis patients has increased from 30% to 90%; heart failure can be reversed; some reports have shown ventricular function improving, even when treatment was started after systolic dysfunction



• Moderate enlargement of heart, predominantly due to left ventricular hypertrophy and dilation

• Myocardium is characteristically dark brown; consistency may be firm or soft

• Fibrosis may be seen grossly, beginning in the subepicardium


• Hemosiderin in myocardial cytoplasm

  • In order of decreasing severity: ventricles, interventricular septum, atrioventricular (AV) node, bundle branch, atria, sinoatrial (SA) node

  • In order of appearance: subepicardial, subendocardial, midmyocardial

    – Systolic function is preserved until late

    – Dilated or restrictive cardiomyopathy

  • Iron accumulation and fibrosis of conduction system

    – AV node and His–Purkinje system → arrhythmia

  • SA node very rarely affected → sick sinus

  • Vessels:

    – Coronary arteries are rarely affected

    – Adventitia, endothelium, perithelium, and histiocytes in the heart and aorta and other great vessels sometimes contain small amount of stainable iron

  • In treated patients less iron may be present

Immunopathology/special stains

• Prussian blue stain highlights hemosiderin deposits

• Appearance after Prussian blue staining

  • Fine grains at two poles of cardiomyocyte nuclei, tapering away

  • Myocytes may be fully packed with fine granules; little change in shape

  • Small quantities of coarse extracellular hemosiderin deposition are sometimes seen in connective tissue in lymphatics, fibroblasts, and monocytes and interstitially

Main differential diagnoses

• Hemosiderosis: excessive tissue iron storage without scarring or organ failure

• Lipofuscin: negative for Prussian blue


Fig 1 Cardiac hemochromatosis. Gross photograph of the heart cut in cross-sections from a patient with hemochromatosis. Note multiple areas of brown pigmentation.


Fig 2 Cardiac hemochromatosis. Mild interstitial fibrosis is seen in this patient with hemochromatosis.


Fig 3 Cardiac hemochromatosis. High powers show intracellular hemosiderin in paranuclear region, deposited in a spindle-shaped pattern visible in longitudinal sections of the myocardium (A) and myocytes cut in cross-sections (B).


Fig 4 Cardiac hemochromatosis. Prussian blue stain is positive: low (A) and high (B) powers.

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