Why Hemochromatosis Causes Dilated Cardiomyopathy
Iron accumulates directly within cardiac myocytes (sarcoplasmic deposition, not interstitial), causing oxidative damage that initially impairs diastolic function through restrictive cardiomyopathy, then progressively destroys contractile machinery leading to dilated cardiomyopathy with systolic dysfunction. 1
Mechanism of Cardiac Iron Deposition
Iron enters cardiac myocytes through L-type calcium channels when transferrin becomes saturated during iron overload. 1 This is critical to understand—under normal conditions, cardiac iron is regulated through transferrin-mediated uptake, but in hemochromatosis, non-transferrin-bound iron (ferrous form) floods into myocytes through calcium channels once transferrin saturation exceeds capacity 1.
Cellular Pathophysiology
Iron deposits in the sarcoplasm (cytoplasm) of myocytes, not in the interstitial space, distinguishing this as a storage disease rather than an infiltrative process 1.
Iron-induced lipid peroxidation damages cellular membranes, lysosomes, mitochondria, and microsomes, leading to direct myocyte injury and death 1.
Oxidative stress from accumulated iron impairs energy metabolism and calcium handling, progressively destroying contractile function 2, 3.
Progressive Cardiac Dysfunction Pattern
The natural history follows a predictable sequence: myocardial iron accumulation → restrictive cardiomyopathy with diastolic dysfunction → dilated cardiomyopathy with systolic dysfunction. 1
Early Phase (Restrictive Pattern)
Diastolic dysfunction appears first, often while patients remain asymptomatic, as iron stiffens the myocardium 1, 3.
Myocardial iron overload precedes clinical cardiac dysfunction, making early detection crucial 1.
Ventricular diastolic dysfunction can be present in asymptomatic patients with normal ejection fraction 1.
Late Phase (Dilated Pattern)
Progressive myocyte death and replacement fibrosis cause ventricular dilatation with impaired systolic function 1, 3.
Dilated cardiomyopathy develops with reduced ejection fraction and reduced fractional shortening 4, 3.
Once heart failure develops, there is rapid deterioration with average survival less than one year if untreated 3.
Conduction System Involvement
Iron deposits throughout the cardiac conduction system, particularly the atrioventricular node, causing arrhythmias independent of heart failure severity 1.
Extreme bradycardia, heart blocks, atrial fibrillation, ventricular arrhythmias, and sudden death occur even without congestive heart failure 1.
Pacemaker implantation is often necessary in severe juvenile hemochromatosis due to extreme bradycardia and heart blocks 1.
Clinical Context: C282Y Homozygosity
In adult HFE-related hemochromatosis (C282Y homozygous), cardiac involvement is rare compared to juvenile forms, because the rate and magnitude of iron accumulation is slower 1.
Cardiac manifestations appear mainly in severe or advanced adult disease that has gone untreated for years 1.
The heart is particularly sensitive to rapid and massive increases in plasma iron early in disease development 1.
Juvenile hemochromatosis (HJV and HAMP mutations) causes severe heart failure before age 30 due to more rapid iron accumulation, potentially requiring heart transplant 1.
Critical Pitfalls to Avoid
Do not wait for symptoms to screen for cardiac involvement—myocardial iron overload and diastolic dysfunction precede clinical heart failure 1, 3. Perform echocardiography and cardiac MRI R2* in all patients with significant iron overload, regardless of symptoms 1.
Do not assume normal ferritin excludes cardiac iron—there are no recognized threshold levels for serum ferritin or liver iron concentration that reliably predict cardiac iron deposition 1. The relationship depends on the rate and duration of iron accumulation, not just absolute levels 1.
Avoid vitamin C supplementation during iron removal therapy—pharmacologic doses of vitamin C accelerate iron mobilization to levels that may saturate transferrin, increasing pro-oxidant activity and risk of cardiac dysrhythmias 1, 5.
Recognize that phlebotomy before cirrhosis develops can prevent cardiac complications entirely, but once dilated cardiomyopathy is established, structural changes may persist despite iron removal 1, 6.