Iron Overload Cardiomyopathy: The Silent Threat

Introduction

Cardiomyopathies can be classified as either primary or secondary heart muscle illnesses. Primary cardiomyopathies are typically caused by unknown reasons, and treatment is limited to basic heart failure management. Secondary cardiomyopathies, on the other hand, pinpoint the underlying cause and enable a more focused, effective strategy that, when administered early, may prevent the development of heart failure. Iron overload cardiomyopathy (IOC) is a new term used to describe a type of secondary cardiomyopathy caused by iron accumulation in the heart, primarily due to genetically determined iron metabolism issues or frequent transfusions. Iron overload is a common problem, especially in conjunction with certain hematologic diseases, and it necessitates proper identification and efficient therapy as soon as possible. Iron overload cardiomyopathy (IOC) is distinguished by the following symptoms:

• Left ventricular (LV) remodeling.

• Dilated cardiomyopathy.

• Chamber dilatation.

• Decreased left ventricular ejection fraction (LVEF).

What Is the Prevalence of Iron Overload Cardiomyopathy (IOC)?

• Iron overload cardiomyopathy (IOC) is also a major cause of morbidity and causes one-third of deaths in hereditary hemochromatosis, particularly in young male patients.

• It is the leading cause of mortality in thalassemia major (a hereditary blood disorder caused due to lack of hemoglobin production).

• It is also a major cause of death in other conditions associated with secondary iron overload.

What Are Primary and Secondary Hemochromatosis?

• Primary (Hereditary) Hemochromatosis - It is a hereditary disorder that causes an excess of iron production in the body. It is classified as an infiltrative cause of restrictive cardiomyopathy. Furthermore, the cause of primary iron overload cardiomyopathy (IOC) has been identified as four varieties of gene mutations that are as follows:

1. Type 1 - It is caused by mutations in the HFE gene on chromosome 6, and it is the most common type.

2. Type 2 - It is caused by mutations in the HAMP gene on chromosome 19, which produces hepcidin.

3. Type 3 - It is caused by mutations in the TfR2 gene on chromosome 7, which codes for transferrin receptor 2.

4. Type 4 - It is caused by mutations in the ferroportin-encoding SLC40A1 gene on chromosome 2.

Types 1, 3, and 4 appear in adulthood, usually during the fourth or fifth decade of life, whereas type 2, sometimes known as juvenile hemochromatosis, appears much earlier, in the second or third decade of life. Hepatic involvement predominates in types 1 and 3, although endocrine and cardiac problems are more prominent in type 2, and heart failure is a common cause of death before the age of 30.

• Secondary Iron Overload (Hemosiderosis) - It is caused by the following conditions:

1. Severe diastolic left ventricular dysfunction.

2. High parenteral iron administration.

3. Aplastic anemia (inability of bone marrow to make red blood cells).

4. Inherited hemoglobinopathies (blood disorders).

5. Myelodysplastic syndromes (MDS) (abnormal production of red blood cells in bone marrow).

6. Myelofibrosis (a rare type of cancer of bone marrow).

7. Blackfan-Diamond anemia (the bone marrow fails to produce enough red blood cells).

8. Sideroblastic anemia (caused due to abnormal utilization of iron).

What Happens Due to an Overload of Iron?

Iron is an essential component of hemoglobin, which plays a significant role in the formation of red blood cells, oxygen transfer, and storage. Iron also plays important roles in various enzymatic systems and metabolic activities. Consequently, an iron shortage impairs functional status, so iron replacement therapy is advantageous to the body. Iron homeostasis is critical, and it is governed by a complicated system involving:

• Iron absorption.

• Iron transportation.

• Iron storage.

• Engagement of multiple regulatory proteins.

However, iron is a two-sided element, and disruption in iron homeostasis (balance in the body) that results in excessive iron intake and storage are harmful to various tissues. The accumulation of excess bodily iron in various organs is known as "iron overload." It occurs as a result of the following:

• Enhanced intestinal absorption of iron.

• Parenteral injection of iron.

• Higher dietary intake.

Excess iron accumulation largely affects the heart, liver, and endocrine glands, and hence iron-loading diseases are primarily manifested as the following:

• Cardiac dysfunction and failure.

• Liver dysfunction and cirrhosis.

• Hypothyroidism.

• Hypogonadism (underdevelopment of gonads).

• Diabetes mellitus.

What Are the Clinical Features of Iron Overload Cardiomyopathy (IOC)?

• Bronze skin.

• Liver cirrhosis (liver damage due to excess fibrous formation).

• Diabetes mellitus.

How Is Iron Overload Cardiomyopathy (IOC) Diagnosed?

Iron overload cardiomyopathy (IOC) is diagnosed by the presence of the following criteria:

• Iron overload (serum ferritin > 300 ng/mL, transferrin saturation > 55 percent).

• Cardiac siderosis (cardiac iron accumulation 20 ms).

• Evidence of heart disease such as LVEF (left ventricular ejection fraction).

What Is the Treatment of Iron Overload Cardiomyopathy (IOC)?

• Treatment of Heart Failure With Iron Removal

1. Phlebotomy and Iron Chelation - These procedures promote whole-body iron elimination.

2. Early Initiation of Phlebotomy Therapy - It can correct left ventricular dysfunction in individuals with advanced iron excess.

3. Maintenance Phlebotomy - It should be performed in patients with primary hemochromatosis following primary iron depletion to prevent iron reaccumulation, with a reasonable target of keeping serum ferritin concentration at 50 ng/mL or below.

• Iron Chelation Therapy - It involves the intravenous iron chelator Deferoxamine or the oral iron chelators Deferiprone and Deferasirox, which is the major therapy offered in patients with secondary iron overload. In individuals with secondary iron overload, chelation has been found to enhance ventricular function, avoid ventricular arrhythmias, and reduce mortality.

• Angiotensin-Converting Enzyme Inhibitors and B-Adrenergic Blockers - Early use of angiotensin-converting enzyme inhibitors and b-adrenergic blockers, in addition to device therapy, should be routine therapy for patients with iron overload-induced heart failure.

In cases of severe refractory iron-overload cardiomyopathy, a combination heart and liver transplant may be considered. There is also a danger of iron-overload cardiomyopathy recurrence in the transplanted heart. The use of exchange blood transfusions in patients with sickle cell anemia may help reduce the iron-overload burden.

Conclusion

Primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis) are causing overloading of excessive iron deposition in a wide range of tissues, including the heart and endocrine tissues. On a global scale, iron-overload cardiomyopathy is a significant and potentially reversible cause of heart failure, characterized by heart dysfunction, increased susceptibility to irregular heartbeat, and late-stage dilated cardiomyopathy. Early detection of iron-overload cardiomyopathy is crucial because cardiac dysfunction is reversible if appropriate therapy is started before overt heart failure develops.