Definition
• Excessive iron in cardiomyocytes with tissue damage and impaired organ function
Pathogenesis
• 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
Epidemiology
• 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
Presentation
• 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
Pathology
Gross
• 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
Histology
• 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.