Iron Overload

Iron overload, also known as hemosiderosis, is a condition in which the supply of iron exceeds the body's needs, resulting in an excessive accumulation of total body iron. This excess iron is widely deposited in the parenchymal cells of vital organs and tissues, which may or may not be accompanied by organ dysfunction. In humans, the normal transferrin saturation in serum is approximately 30%. Iron overload is indicated when transferrin saturation exceeds 45% in females or 50% in males. When serum transferrin saturation surpasses 60%, non-transferrin-bound iron accumulates in the circulation, leading to cellular damage.

Based on etiology, iron overload conditions are classified into two main categories: primary and secondary. Primary iron overload is caused by congenital metabolic disorders leading to excessive iron accumulation in the body, which is called as hereditary hemochromatosis. Secondary iron overload often results from factors such as multiple blood transfusions, long-term iron supplementation, excessive dietary iron intake, or certain hematological disorders.

When the iron content in the human body exceeds the binding capacity of transferrin, the excess iron initially accumulates in the liver, subsequently affecting endocrine organs such as the thyroid and pituitary glands, and finally depositing in the heart. This not only accelerates the deterioration of the primary disease but also causes damage to the tissue cells of these organs, leading to conditions and complications such as arrhythmias, heart failure, liver fibrosis, cirrhosis, diabetes mellitus, hematopoietic suppression, increased risk of infection, poor outcomes following hematopoietic stem cell transplantation (HSCT), and accelerated leukemic transformation in myelodysplastic syndrome (MDS). These complications can significantly impact patient survival.

UHereditary Hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder, which is one of the most common genetic diseases in the United States. Mutations in the HFE gene on chromosome 6 are the primary cause of hereditary hemochromatosis, with the missense mutation C282Y homozygosity accounting for approximately 80% to 85% of cases among HH patients. Non-HFE hemochromatosis is caused by mutations in other genes such as HJV, HAMP, TfR2, and SLC40A1. The incidence of non-HFE hemochromatosis is significantly lower than that of HFE-related hemochromatosis and does not exhibit regional or ethnic disparities.

Secondary Iron Overload

Normal individuals absorb and utilize 1-2 mg of iron daily, which represents about 10-15% of the iron content in a normal diet. However, some anemic patients absorb twice the amount of iron as healthy individuals, around 3-4 mg daily. Furthermore, patients with common transfusion-dependent hematological disorders such as thalassemia (TDT), aplastic anemia (AA), and MDS absorb additional iron during long-term blood transfusion therapy. Since the human body lacks an effective mechanism for iron excretion, the iron introduced through blood transfusions cannot be eliminated and consequently accumulates in the body. After 10-20 transfusions, the iron intake can reach 4-5 grams, leading to the development of iron overload in these patients.

Epidemiology of Iron Overload

Hemochromatosis is the most prevalent genetic disorder in North America. It is estimated that 16 million Americans are affected by varying degrees of hereditary or secondary iron overload. Patients with hereditary hemochromatosis typically have Northern European ancestry. A study published in 2018 found that the frequency of C282Y homozygosity in European countries was 0.4%, with a heterozygote frequency of 9.2%, while in North America, the frequencies were 0.5% and 9%, respectively. It is estimated that one in 200 U.S. whites has iron overload, with 10% to 14% being carriers of genetic mutations.

Diagnosis of Iron Overload

Clinically, measuring serum ferritin (SF) levels and transferrin saturation (TS) are the preferred initial diagnostic methods for iron overload. Serum ferritin levels exceeding 300 ng/mL in men or 200 ng/mL in women, coupled with transferrin saturation above 45%, are highly suggestive of hereditary hemochromatosis. Liver biopsy is the gold standard for quantitative liver iron assessment. However, due to the invasiveness and associated risks of liver biopsy, MRI T2* is the preferred non-invasive method for iron quantification. MRI T2* is a technique used to assess liver and myocardial iron based on how iron affects the water protons in the tissue of interest. A liver T2* value between 4 and 8 ms suggests mild iron overload, a value between 2 and 4 ms indicates moderate iron overload, and a value below 2 ms signifies severe iron overload. A myocardial T2* value less than 20 ms is indicative of myocardial iron overload, and a value less than 10 ms suggests severe cardiac iron overload.

Launched Drugs

Once iron overload occurs, patients require timely therapy to reduce the body's iron burden, improve vital organ function, and prolong survival. Deferoxamine, deferiprone, and deferasirox are usually used to treat iron overload as iron chelators, although they are prone to side effects. Deferoxamine is a chelating agent first launched in the U.S. Deferiprone is a chelating agent that was first launched in India as Kelfer(R) for the treatment of iron overload in patients with homozygous beta-thalassemia. Deferasirox is the first and only once-daily oral iron chelator, which is commercialized by Novartis for the treatment of chronic iron overload due to blood transfusions in chronic anemias in adult and pediatric patients two years of age and older.

Structure	Generic Name	CAS Registry Number	Molecular Formula	Molecular Weight	Launched Year
	deferasirox (Rec INN; USAN)	201530-41-8	C21 H15 N3 O4	373.362	2005
	deferiprone (Rec INN; USAN)	30652-11-0	C7 H9 N O2	139.152	1995
	deferoxamine (USAN)	70-51-9	C25 H48 N6 O8	560.684	1963